Peroxisomal Acyl-CoA Oxidase Deficiency

Metabolic Disorder MONDO:0009919 Pathograph 27 hereditary disease metabolic disorder disorder of peroxisomal beta oxidation

Peroxisomal acyl-CoA oxidase deficiency is a rare autosomal recessive peroxisomal fatty-acid oxidation disorder caused by ACOX1 deficiency. Loss of straight-chain acyl-CoA oxidase activity impairs peroxisomal oxidation of very-long-chain fatty acids, produces VLCFA accumulation, and causes an infantile neurodegenerative leukodystrophy with hypotonia, seizures, developmental delay, sensory loss, and regression.

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5
Pathophys.
13
Phenotypes
27
Pathograph
1
Genes
2
Treatments
3
Differentials
2
Models
1
Deep Research
⚙

Pathophysiology

5
ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency
Biallelic ACOX1 pathogenic variants reduce straight-chain acyl-CoA oxidase activity, disrupting the first acyl-CoA oxidase step of peroxisomal very-long-chain fatty-acid beta-oxidation.
ACOX1 link
fatty acid beta-oxidation using acyl-CoA oxidase link ↓ DECREASED very long-chain fatty acid beta-oxidation link ↓ DECREASED
acyl-CoA oxidase activity link ↓ DECREASED
peroxisome link
Downstream
Very-Long-Chain Fatty Acid Accumulation ACOX1 deficiency blocks peroxisomal VLCFA oxidation.
Show evidence (2 references)
PMID:17458872 SUPPORT Human Clinical
"Peroxisomal acyl-coenzyme A (acyl-CoA) oxidase deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation due to a deficiency of straight-chain acyl-CoA oxidase (SCOX)."
The cohort paper identifies straight-chain acyl-CoA oxidase deficiency as the causal biochemical lesion.
PMID:18536048 SUPPORT Human Clinical
"Studies in fibroblasts from the two patients revealed a deficiency of one of the two peroxisomal acyl-CoA oxidases, that is, straight-chain acyl-CoA oxidase (ACOX1)."
Patient fibroblast studies directly support ACOX1 enzyme deficiency.
Very-Long-Chain Fatty Acid Accumulation
Impaired peroxisomal beta-oxidation causes accumulation of very-long-chain fatty acids, including abnormal plasma VLCFA values and deficient C26:0 oxidation in cellular testing.
very long-chain fatty acid beta-oxidation link ↓ DECREASED
peroxisome link
Downstream
Fibroblast IL-1 Cytokine Inflammatory Response VLCFAs can induce IL-1 cytokine expression and inflammatory signaling in patient fibroblast models.
Neurodegenerative White Matter Disease VLCFA accumulation contributes to inflammatory demyelination and progressive CNS disease.
Retinitis Pigmentosa The ACOX1 deficiency phenotype spectrum includes retinal degeneration with retinitis pigmentosa and vision abnormalities.
Facial Dysmorphism Facial dysmorphism is part of the broader reported ACOX1 deficiency phenotype spectrum.
Hepatic Dysfunction Hepatic dysfunction is part of the broader reported ACOX1 deficiency phenotype spectrum.
Adrenal Insufficiency Adrenal insufficiency is part of the broader reported ACOX1 deficiency phenotype spectrum.
Peripheral Neuropathy Peripheral neuropathy is reported in severe ACOX1 deficiency.
Show evidence (2 references)
PMID:17458872 SUPPORT Human Clinical
"The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids."
This supports VLCFA accumulation as the defining biochemical abnormality.
PMID:16773508 SUPPORT Human Clinical
"Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in..."
This patient report supports elevated VLCFAs and deficient C26:0 oxidation while distinguishing the isolated ACOX1 beta-oxidation defect from broader peroxisomal dysfunction.
Fibroblast IL-1 Cytokine Inflammatory Response
Patient fibroblast transcriptomic and PCR-array studies show IL-1 pathway activation with increased IL-6 and IL-8 secretion, linking ACOX1 loss and VLCFA exposure to inflammatory signaling.
fibroblast link
inflammatory response link ↑ INCREASED interleukin-1-mediated signaling pathway link ↑ INCREASED cytokine-mediated signaling pathway link ↑ INCREASED
Experimental models
Patient fibroblast inflammatory response model PRIMARY CELL CULTURE Patient fibroblasts assay IL-1, IL-6, and IL-8 inflammatory signaling caused by ACOX1 deficiency.
Downstream
Neurodegenerative White Matter Disease IL-1-centered inflammation is a plausible contributor to inflammatory demyelination.
Show evidence (2 references)
PMID:22508517 SUPPORT In Vitro
"Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines."
The patient-fibroblast study directly supports activation of IL-1 inflammatory signaling.
PMID:22508517 SUPPORT In Vitro
"Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central."
This connects ACOX1 activity loss to the IL-1-centered inflammatory response.
Microglial Disease-Associated Inflammatory Phenotype
Acox1-deficient and other peroxisomal beta-oxidation-defect microglial cell models show broad lipid, immune, lysosomal, autophagy, and disease-associated microglial programs, suggesting microglial pathology as an additional contributor to peroxisomal leukodystrophy.
microglial cell link
inflammatory response link ↑ INCREASED autophagy link ⚠ ABNORMAL cholesterol homeostasis link ⚠ ABNORMAL
Experimental models
Acox1-deficient BV-2 microglial cell model CELL LINE Mutant microglia model lipid, immune, autophagy, and DAM-like programs.
Downstream
Neurodegenerative White Matter Disease Pathological microglial programs may amplify neuroinflammation and white-matter injury.
Show evidence (2 references)
PMID:37138705 SUPPORT In Vitro
"In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature."
RNA-seq in mutant BV-2 microglial models supports immune, lipid, and autophagy reprogramming.
PMID:37138705 SUPPORT In Vitro
"In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders."
The model paper explicitly interprets mutant microglia as adopting a pathological phenotype relevant to peroxisomal-disorder pathogenesis.
Neurodegenerative White Matter Disease
ACOX1 deficiency produces progressive central nervous system disease with inflammatory demyelination, cerebral and cerebellar white-matter involvement, cortical and cerebellar atrophy, neuronal loss, and secondary functional decline.
oligodendrocyte link microglial cell link
inflammatory response link ↑ INCREASED
brain link white matter of cerebellum link cerebellum link
Downstream
Leukodystrophy Inflammatory demyelination and progressive white-matter injury produce the leukodystrophy phenotype.
Cerebral and Cerebellar White Matter Abnormalities Progressive demyelination is visible as cerebral, cerebellar, brainstem, and subcortical white-matter abnormalities on MRI.
Developmental Regression Progressive neurodegeneration causes loss of acquired developmental skills in early childhood.
Early-Onset Hypotonia Infantile CNS dysfunction presents early with hypotonia.
Infantile Seizures Infantile CNS involvement includes seizures during the early disease phase.
Psychomotor Delay Early neurologic disease delays acquisition of psychomotor milestones before regression.
Visual Impairment Progressive neurodegeneration can lead to loss of visual function during regression.
Hearing Impairment Progressive neurodegeneration can lead to loss of hearing during regression.
Show evidence (3 references)
PMID:22508517 SUPPORT In Vitro
"Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination."
This connects ACOX1 deficiency and VLCFA accumulation to inflammatory demyelination.
PMID:24619150 SUPPORT Human Clinical
"Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy."
This sibling comparison supports fatal neurodegeneration and cerebral and cerebellar atrophy.
PMID:24619150 SUPPORT Human Clinical
"Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
Longitudinal MRI supports progressive CNS demyelination and white matter tract involvement.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Peroxisomal Acyl-CoA Oxidase Deficiency 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

13
Digestive 1
Hepatic Dysfunction OCCASIONAL Decreased liver function (HP:0001410)
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
This literature summary reports hepatic dysfunction as a less frequent finding; the HPO binding uses decreased liver function rather than hepatomegaly to match the quoted clinical statement.
Ear 1
Hearing Impairment FREQUENT Hearing impairment (HP:0000365)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
This supports hearing impairment as part of the reported phenotype spectrum.
Endocrine 1
Adrenal Insufficiency OCCASIONAL Adrenal insufficiency (HP:0000846)
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
This literature summary reports adrenal insufficiency as a less frequent finding in ACOX1 deficiency.
Eye 2
Retinitis Pigmentosa FREQUENT Rod-cone dystrophy (HP:0000510)
Sequelae: Visual Impairment
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
This literature summary identifies retinitis pigmentosa as a common manifestation in reported ACOX1 deficiency.
Visual Impairment FREQUENT Visual impairment (HP:0000505)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
This supports visual impairment as a common manifestation in reported ACOX1 deficiency.
Head and Neck 1
Facial Dysmorphism OCCASIONAL Abnormal facial shape (HP:0001999)
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
This literature summary reports facial dysmorphism as a less frequent finding in ACOX1 deficiency.
Musculoskeletal 1
Early-Onset Hypotonia Hypotonia (HP:0001252)
Onset: INFANTILE
Show evidence (1 reference)
PMID:18536048 SUPPORT Human Clinical
"Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
The two-patient report directly supports early hypotonia as part of the disease phenotype.
Nervous System 6
Infantile Seizures Seizure (HP:0001250)
Onset: INFANTILE
Show evidence (1 reference)
PMID:18536048 SUPPORT Human Clinical
"Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
This directly supports seizures in affected infants.
Psychomotor Delay Global developmental delay (HP:0001263)
Onset: INFANTILE
Show evidence (1 reference)
PMID:18536048 SUPPORT Human Clinical
"Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
Psychomotor delay in both reported cases supports global developmental delay.
Developmental Regression Developmental regression (HP:0002376)
Course: PROGRESSIVE Onset: INFANTILE
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"the natural history of the disease follows a fairly consistent pattern of infantile-onset hypotonia, seizures, delayed acquisition of early developmental milestones, followed by rapid developmental regression between 24 and 48 months of age."
This directly supports early-childhood developmental regression after limited early skill acquisition.
Leukodystrophy Leukodystrophy (HP:0002415)
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22508517 SUPPORT In Vitro
"Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination."
This supports inflammatory demyelination as part of the ACOX1 deficiency phenotype and mechanism.
Cerebral and Cerebellar White Matter Abnormalities Abnormal cerebral white matter morphology (HP:0002500)
Course: PROGRESSIVE
Show evidence (2 references)
PMID:16773508 SUPPORT Human Clinical
"The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly..."
The case report directly describes cerebral and cerebellar white matter abnormalities.
PMID:24619150 SUPPORT Human Clinical
"Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
Serial MRI confirms progressive white-matter involvement.
Peripheral Neuropathy Peripheral neuropathy (HP:0009830)
Show evidence (1 reference)
PMID:16773508 SUPPORT Human Clinical
"The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly..."
The fatal case report explicitly lists peripheral neuropathy among the clinical manifestations.
🧬

Genetic Associations

1
ACOX1 pathogenic variants (Biallelic loss-of-function variants cause autosomal recessive ACOX1 deficiency.)
Autosomal recessive
Show evidence (1 reference)
PMID:17458872 SUPPORT Human Clinical
"No clear genotype-phenotype correlation was observed."
The cohort analysis supports limited genotype-phenotype correlation.
💊

Treatments

2
Multidisciplinary Supportive Care
Action: supportive care MAXO:0000950
Care is supportive and symptom-directed, including seizure management, developmental support, feeding and respiratory support, and surveillance for sensory and neurologic decline. No disease-modifying standard therapy is established.
Show evidence (1 reference)
PMID:24619150 PARTIAL Human Clinical
"Supportive care was initially recommended due to the degenerative natural history of the disorder."
This supports supportive care as the default management approach, but does not establish a disease-modifying effect.
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantation MAXO:0000747
HSCT has been attempted in ACOX1 deficiency but did not halt the neurodegenerative course; available evidence suggests possible reduction of white-matter inflammation rather than disease arrest.
Mechanism Target:
INHIBITS Neurodegenerative White Matter Disease — HSCT may reduce inflammatory white-matter disease but does not prevent progressive neurodegeneration.
Show evidence (1 reference)
PMID:24619150 PARTIAL Human Clinical
"Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain."
This directly supports a partial anti-inflammatory effect without disease arrest.
Show evidence (1 reference)
PMID:24619150 PARTIAL Human Clinical
"Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain."
HSCT evidence is limited and supports only partial modulation of brain inflammation.
🔬

Biochemical Markers

3
Elevated very-long-chain fatty acids (INCREASED)
Context: Increased plasma and cellular VLCFAs are the hallmark biochemical finding of ACOX1 deficiency, although plasma screening can be misleading in some cases.
Pathograph Readouts
Readout Of Very-Long-Chain Fatty Acid Accumulation Positive Diagnostic
Elevated VLCFA measurements are the diagnostic biochemical readout of the VLCFA accumulation node.
Show evidence (2 references)
PMID:17458872 SUPPORT Human Clinical
"The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids."
This directly supports increased VLCFAs as the key biochemical abnormality.
PMID:16773508 SUPPORT Human Clinical
"Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in..."
This supports elevated cellular VLCFAs and the isolated beta-oxidation defect.
Deficient C26:0 oxidation (DECREASED)
Context: C26:0 oxidation activity is reduced in fibroblast testing, supporting an isolated peroxisomal beta-oxidation defect.
Pathograph Readouts
Readout Of ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency Negative Diagnostic
Low C26:0 oxidation in fibroblasts reports the impaired ACOX1 straight-chain acyl-CoA oxidase activity.
Show evidence (1 reference)
PMID:16773508 SUPPORT Human Clinical
"Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in..."
This explicitly documents deficient C26:0 oxidation in patient fibroblasts.
Preserved phytanic acid, pristanic acid, and plasmalogen screening markers (NORMAL)
Context: Normal phytanic acid, pristanic acid, and erythrocyte plasmalogen values can occur despite ACOX1 deficiency, creating a diagnostic pitfall.
Pathograph Readouts
Correlates With ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency Threshold Dependent Diagnostic
Normal phytanic acid, pristanic acid, and plasmalogen screening markers help distinguish isolated ACOX1 beta-oxidation deficiency from broader peroxisomal dysfunction but do not exclude disease.
Show evidence (1 reference)
PMID:18536048 SUPPORT Human Clinical
"Plasma very-long-chain fatty acids were abnormal in both patients, whereas the plasma levels of phytanic acid, pristanic acid, the bile acid intermediates DHCA and THCA, and erythrocyte plasmalogen levels were normal."
This supports preservation of other peroxisomal screening markers in isolated ACOX1 deficiency.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Peroxisomal Acyl-CoA Oxidase Deficiency:

Adrenoleukodystrophy MONDO:0018544
Overlapping Features X-linked adrenoleukodystrophy overlaps through VLCFA accumulation, inflammatory CNS demyelination, and progressive neurologic decline, but is caused by ABCD1 transporter dysfunction rather than isolated ACOX1 enzyme deficiency.
Distinguishing Features
  • ACOX1 deficiency shows deficient straight-chain acyl-CoA oxidase activity and ACOX1 variants; X-linked adrenoleukodystrophy is ABCD1-related.
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"Inherited deficiencies of peroxisomal straight chain VLCFA β-oxidation include only straight-chain acyl-CoA oxidase (ACOX1) deficiency (also known as “pseudo-neonatal ALD”) and X-linked adrenoleukodystrophy (X-ALD). These two disorders share symptoms and biochemical characteristics, with varying..."
This directly supports X-ALD/adrenoleukodystrophy as a key overlapping differential diagnosis.
D-Bifunctional Protein Deficiency Not Yet Curated MONDO:0009855
Overlapping Features D-bifunctional protein deficiency is another peroxisomal beta-oxidation disorder with overlapping neonatal hypotonia, seizures, liver involvement, VLCFA abnormalities, and severe neurodevelopmental disease.
Distinguishing Features
  • ACOX1 deficiency affects the acyl-CoA oxidase step, whereas D-bifunctional protein deficiency is HSD17B4-related.
Show evidence (1 reference)
PMID:24619150 SUPPORT Human Clinical
"This is further supported by the progression of pyramidal tract degeneration from medullary to subcortical levels, and sequential loss of white matter proceeding from the dentate nuclei and superior cerebellar peduncles to involve the cerebellar white matter and remaining peduncles, and confirms..."
This supports bifunctional enzyme deficiency as a related peroxisomal-disorder comparator in neuroimaging and white-matter progression.
Peroxisome Biogenesis Disorder MONDO:0019234
Overlapping Features Peroxisome biogenesis disorders can present with overlapping neonatal neurologic disease and peroxisomal biochemical abnormalities, but involve broader peroxisome assembly defects rather than isolated ACOX1 deficiency.
Distinguishing Features
  • Normal plasmalogen synthesis and normal phytanic/pristanic acid oxidation with deficient C26:0 oxidation favors isolated ACOX1 beta-oxidation deficiency over a generalized peroxisome biogenesis disorder.
Show evidence (1 reference)
PMID:16773508 SUPPORT Human Clinical
"Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in..."
This supports biochemical differentiation of isolated beta-oxidation defects from broader peroxisomal biogenesis dysfunction.
🧫

Experimental Models

2
Patient fibroblast inflammatory response model PRIMARY_CELL_CULTURE
Cultured patient fibroblasts model the ACOX1-deficient inflammatory response and demonstrate IL-1 pathway activation and cytokine modulation by MAPK, p38MAPK, and JNK inhibitors.
fibroblast ↗
Organism
human ↗
Cell source
Patient-derived fibroblasts
Publication
PMID:22508517 ↗
Pathograph links
Fibroblast IL-1 Cytokine Inflammatory Response Patient fibroblasts assay IL-1, IL-6, and IL-8 inflammatory signaling caused by ACOX1 deficiency.
Findings
IL-1 inflammatory pathway activation
IL-6 and IL-8 cytokine secretion
MAPK/p38MAPK/JNK inhibitor modulation
Show evidence (1 reference)
PMID:22508517 SUPPORT In Vitro
"Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors."
This supports patient fibroblasts as a model of ACOX1-deficient inflammatory signaling and pharmacologic modulation.
Acox1-deficient BV-2 microglial cell model CELL_LINE
Mutant BV-2 microglial cell lines model peroxisomal beta-oxidation defects, VLCFA accumulation, lipid/immune/autophagy reprogramming, and a disease-associated microglial signature.
microglial cell ↗
Cell source
BV-2 microglial cell line
Publication
PMID:37138705 ↗
Pathograph links
Microglial Disease-Associated Inflammatory Phenotype Mutant microglia model lipid, immune, autophagy, and DAM-like programs.
Findings
VLCFA accumulation
DAM-like transcriptional signature
cholesterol accumulation in plasma membranes
altered autophagy patterns
Show evidence (1 reference)
PMID:37138705 SUPPORT In Vitro
"We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation."
This supports the BV-2 mutant microglial model as relevant to peroxisomal beta-oxidation defects including Acox1 loss.
{ }

Source YAML

click to show 
name: Peroxisomal Acyl-CoA Oxidase Deficiency
creation_date: "2026-05-10T20:13:58Z"
updated_date: "2026-05-19T16:05:46Z"
description: >-
  Peroxisomal acyl-CoA oxidase deficiency is a rare autosomal recessive
  peroxisomal fatty-acid oxidation disorder caused by ACOX1 deficiency. Loss of
  straight-chain acyl-CoA oxidase activity impairs peroxisomal oxidation of
  very-long-chain fatty acids, produces VLCFA accumulation, and causes an
  infantile neurodegenerative leukodystrophy with hypotonia, seizures,
  developmental delay, sensory loss, and regression.
category: Metabolic Disorder
synonyms:
  - ACOX1 deficiency
  - Pseudoneonatal adrenoleukodystrophy
  - Pseudo-neonatal ALD
  - P-NALD
  - Straight-chain acyl-CoA oxidase deficiency
parents:
  - hereditary disease
  - metabolic disorder
  - disorder of peroxisomal beta oxidation
disease_term:
  preferred_term: peroxisomal acyl-CoA oxidase deficiency
  term:
    id: MONDO:0009919
    label: peroxisomal acyl-CoA oxidase deficiency
epidemiology:
  - name: Ultra-rare reported-patient disorder
    description: >-
      Published clinical literature supports extreme rarity rather than a
      robust population prevalence estimate.
    notes: No population-level prevalence or incidence estimate was identified in the Falcon report.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Since the disorder was first recognized, a total of 31 patients have been reported"
        explanation: >-
          This sibling-comparison study summarized the literature and supports
          the disorder as ultra-rare.
progression:
  - phase: Infantile-onset neurologic disease
    age_range: infancy
    notes: >-
      Most affected children present in infancy with hypotonia, seizures, and
      delayed acquisition of developmental milestones.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "the natural history of the disease follows a fairly consistent pattern of infantile-onset hypotonia, seizures, delayed acquisition of early developmental milestones, followed by rapid developmental regression between 24 and 48 months of age."
        explanation: >-
          This directly supports infantile onset and the typical early clinical
          course.
  - phase: Early-childhood regression and fatal neurodegeneration
    age_range: early childhood
    notes: >-
      Regression usually follows limited early development, with loss of motor,
      communication, visual, and auditory function and death in childhood in
      severe cases.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Advanced patients become non-interactive, non-ambulatory, areflexic, and die in early childhood."
        explanation: >-
          This supports the severe progressive neurodegenerative prognosis in
          classic infantile ACOX1 deficiency.
pathophysiology:
  - name: ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency
    description: >-
      Biallelic ACOX1 pathogenic variants reduce straight-chain acyl-CoA
      oxidase activity, disrupting the first acyl-CoA oxidase step of
      peroxisomal very-long-chain fatty-acid beta-oxidation.
    genes:
      - preferred_term: ACOX1
        term:
          id: hgnc:119
          label: ACOX1
    molecular_functions:
      - preferred_term: acyl-CoA oxidase activity
        term:
          id: GO:0003997
          label: acyl-CoA oxidase activity
        modifier: DECREASED
    cellular_components:
      - preferred_term: peroxisome
        term:
          id: GO:0005777
          label: peroxisome
    biological_processes:
      - preferred_term: fatty acid beta-oxidation using acyl-CoA oxidase
        term:
          id: GO:0033540
          label: fatty acid beta-oxidation using acyl-CoA oxidase
        modifier: DECREASED
      - preferred_term: very long-chain fatty acid beta-oxidation
        term:
          id: GO:0140493
          label: very long-chain fatty acid beta-oxidation
        modifier: DECREASED
    evidence:
      - reference: PMID:17458872
        reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Peroxisomal acyl-coenzyme A (acyl-CoA) oxidase deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation due to a deficiency of straight-chain acyl-CoA oxidase (SCOX)."
        explanation: >-
          The cohort paper identifies straight-chain acyl-CoA oxidase deficiency
          as the causal biochemical lesion.
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Studies in fibroblasts from the two patients revealed a deficiency of one of the two peroxisomal acyl-CoA oxidases, that is, straight-chain acyl-CoA oxidase (ACOX1)."
        explanation: >-
          Patient fibroblast studies directly support ACOX1 enzyme deficiency.
    downstream:
      - target: Very-Long-Chain Fatty Acid Accumulation
        description: ACOX1 deficiency blocks peroxisomal VLCFA oxidation.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:17458872
            reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids."
            explanation: >-
              This directly links the enzyme defect to the defining VLCFA
              biochemical abnormality.
  - name: Very-Long-Chain Fatty Acid Accumulation
    description: >-
      Impaired peroxisomal beta-oxidation causes accumulation of very-long-chain
      fatty acids, including abnormal plasma VLCFA values and deficient C26:0
      oxidation in cellular testing.
    cellular_components:
      - preferred_term: peroxisome
        term:
          id: GO:0005777
          label: peroxisome
    biological_processes:
      - preferred_term: very long-chain fatty acid beta-oxidation
        term:
          id: GO:0140493
          label: very long-chain fatty acid beta-oxidation
        modifier: DECREASED
    chemical_entities:
      - preferred_term: very long-chain fatty acid
        term:
          id: CHEBI:27283
          label: very long-chain fatty acid
        modifier: INCREASED
      - preferred_term: hexacosanoic acid
        term:
          id: CHEBI:31009
          label: hexacosanoic acid
        modifier: INCREASED
    evidence:
      - reference: PMID:17458872
        reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids."
        explanation: >-
          This supports VLCFA accumulation as the defining biochemical
          abnormality.
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system."
        explanation: >-
          This patient report supports elevated VLCFAs and deficient C26:0
          oxidation while distinguishing the isolated ACOX1 beta-oxidation
          defect from broader peroxisomal dysfunction.
    downstream:
      - target: Fibroblast IL-1 Cytokine Inflammatory Response
        description: VLCFAs can induce IL-1 cytokine expression and inflammatory signaling in patient fibroblast models.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:22508517
            reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1α and IL-1β cytokines."
            explanation: >-
              This provides in vitro evidence that VLCFAs can trigger IL-1
              inflammatory cytokine expression.
      - target: Neurodegenerative White Matter Disease
        description: VLCFA accumulation contributes to inflammatory demyelination and progressive CNS disease.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
      - target: Retinitis Pigmentosa
        description: >-
          The ACOX1 deficiency phenotype spectrum includes retinal degeneration
          with retinitis pigmentosa and vision abnormalities.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
            explanation: >-
              The clinical literature summary identifies retinitis pigmentosa
              as a common manifestation in ACOX1 deficiency.
      - target: Facial Dysmorphism
        description: Facial dysmorphism is part of the broader reported ACOX1 deficiency phenotype spectrum.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
            explanation: The literature summary reports facial dysmorphism as a less frequent finding.
      - target: Hepatic Dysfunction
        description: Hepatic dysfunction is part of the broader reported ACOX1 deficiency phenotype spectrum.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
            explanation: The literature summary reports hepatic dysfunction as a less frequent finding.
      - target: Adrenal Insufficiency
        description: Adrenal insufficiency is part of the broader reported ACOX1 deficiency phenotype spectrum.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
            explanation: The literature summary reports adrenal insufficiency as a less frequent finding.
      - target: Peripheral Neuropathy
        description: Peripheral neuropathy is reported in severe ACOX1 deficiency.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:16773508
            reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "peripheral neuropathy"
            explanation: The fatal case report explicitly lists peripheral neuropathy.
  - name: Fibroblast IL-1 Cytokine Inflammatory Response
    description: >-
      Patient fibroblast transcriptomic and PCR-array studies show IL-1 pathway
      activation with increased IL-6 and IL-8 secretion, linking ACOX1 loss and
      VLCFA exposure to inflammatory signaling.
    cell_types:
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
        modifier: INCREASED
      - preferred_term: interleukin-1-mediated signaling pathway
        term:
          id: GO:0070498
          label: interleukin-1-mediated signaling pathway
        modifier: INCREASED
      - preferred_term: cytokine-mediated signaling pathway
        term:
          id: GO:0019221
          label: cytokine-mediated signaling pathway
        modifier: INCREASED
    evidence:
      - reference: PMID:22508517
        reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines."
        explanation: >-
          The patient-fibroblast study directly supports activation of IL-1
          inflammatory signaling.
      - reference: PMID:22508517
        reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central."
        explanation: >-
          This connects ACOX1 activity loss to the IL-1-centered inflammatory
          response.
    downstream:
      - target: Neurodegenerative White Matter Disease
        description: IL-1-centered inflammation is a plausible contributor to inflammatory demyelination.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - name: Microglial Disease-Associated Inflammatory Phenotype
    description: >-
      Acox1-deficient and other peroxisomal beta-oxidation-defect microglial
      cell models show broad lipid, immune, lysosomal, autophagy, and
      disease-associated microglial programs, suggesting microglial pathology as
      an additional contributor to peroxisomal leukodystrophy.
    cell_types:
      - preferred_term: microglial cell
        term:
          id: CL:0000129
          label: microglial cell
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
        modifier: INCREASED
      - preferred_term: autophagy
        term:
          id: GO:0006914
          label: autophagy
        modifier: ABNORMAL
      - preferred_term: cholesterol homeostasis
        term:
          id: GO:0042632
          label: cholesterol homeostasis
        modifier: ABNORMAL
    evidence:
      - reference: PMID:37138705
        reference_title: "Peroxisomal defects in microglial cells induce a disease-associated microglial signature."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature."
        explanation: >-
          RNA-seq in mutant BV-2 microglial models supports immune, lipid, and
          autophagy reprogramming.
      - reference: PMID:37138705
        reference_title: "Peroxisomal defects in microglial cells induce a disease-associated microglial signature."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders."
        explanation: >-
          The model paper explicitly interprets mutant microglia as adopting a
          pathological phenotype relevant to peroxisomal-disorder pathogenesis.
    downstream:
      - target: Neurodegenerative White Matter Disease
        description: Pathological microglial programs may amplify neuroinflammation and white-matter injury.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - name: Neurodegenerative White Matter Disease
    description: >-
      ACOX1 deficiency produces progressive central nervous system disease with
      inflammatory demyelination, cerebral and cerebellar white-matter
      involvement, cortical and cerebellar atrophy, neuronal loss, and secondary
      functional decline.
    cell_types:
      - preferred_term: oligodendrocyte
        term:
          id: CL:0000128
          label: oligodendrocyte
      - preferred_term: microglial cell
        term:
          id: CL:0000129
          label: microglial cell
    locations:
      - preferred_term: brain
        term:
          id: UBERON:0000955
          label: brain
      - preferred_term: white matter of cerebellum
        term:
          id: UBERON:0002317
          label: white matter of cerebellum
      - preferred_term: cerebellum
        term:
          id: UBERON:0002037
          label: cerebellum
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
        modifier: INCREASED
    evidence:
      - reference: PMID:22508517
        reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination."
        explanation: >-
          This connects ACOX1 deficiency and VLCFA accumulation to inflammatory
          demyelination.
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy."
        explanation: >-
          This sibling comparison supports fatal neurodegeneration and cerebral
          and cerebellar atrophy.
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
        explanation: >-
          Longitudinal MRI supports progressive CNS demyelination and white
          matter tract involvement.
    downstream:
      - target: Leukodystrophy
        description: Inflammatory demyelination and progressive white-matter injury produce the leukodystrophy phenotype.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
            explanation: >-
              Serial human MRI directly supports progressive demyelinating
              white-matter disease as the basis of the leukodystrophy
              phenotype.
      - target: Cerebral and Cerebellar White Matter Abnormalities
        description: Progressive demyelination is visible as cerebral, cerebellar, brainstem, and subcortical white-matter abnormalities on MRI.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
            explanation: >-
              Serial MRI directly supports progressive white-matter
              abnormalities as the imaging expression of the demyelinating
              disease node.
      - target: Developmental Regression
        description: Progressive neurodegeneration causes loss of acquired developmental skills in early childhood.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - demyelination, neuronal loss, and axonal degeneration
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "the natural history of the disease follows a fairly consistent pattern of infantile-onset hypotonia, seizures, delayed acquisition of early developmental milestones, followed by rapid developmental regression between 24 and 48 months of age."
            explanation: >-
              The natural-history summary supports developmental regression as
              a downstream clinical phase of the neurodegenerative disease.
      - target: Early-Onset Hypotonia
        description: Infantile CNS dysfunction presents early with hypotonia.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:18536048
            reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
            explanation: >-
              The two-patient report supports hypotonia as an early neurologic
              manifestation of ACOX1 deficiency.
      - target: Infantile Seizures
        description: Infantile CNS involvement includes seizures during the early disease phase.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:18536048
            reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
            explanation: >-
              The report identifies seizures among the early neurologic
              manifestations in affected infants.
      - target: Psychomotor Delay
        description: Early neurologic disease delays acquisition of psychomotor milestones before regression.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:18536048
            reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
            explanation: >-
              The report supports psychomotor delay as part of the early
              neurologic presentation.
      - target: Visual Impairment
        description: Progressive neurodegeneration can lead to loss of visual function during regression.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Developmental regression began at 3.5 years with rapid loss of all vision, hearing, gross motor, and verbal skills."
            explanation: >-
              The detailed clinical course links regression with rapid loss of
              visual function.
      - target: Hearing Impairment
        description: Progressive neurodegeneration can lead to loss of hearing during regression.
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Developmental regression began at 3.5 years with rapid loss of all vision, hearing, gross motor, and verbal skills."
            explanation: >-
              The detailed clinical course links regression with rapid loss of
              hearing.
phenotypes:
  - category: Neurologic
    name: Early-Onset Hypotonia
    description: Hypotonia is an early infantile feature of ACOX1 deficiency.
    phenotype_term:
      preferred_term: Hypotonia
      term:
        id: HP:0001252
        label: Hypotonia
      onset:
        onset_category: INFANTILE
    evidence:
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
        explanation: >-
          The two-patient report directly supports early hypotonia as part of
          the disease phenotype.
  - category: Neurologic
    name: Infantile Seizures
    description: Seizures occur in the early infantile presentation.
    phenotype_term:
      preferred_term: Seizure
      term:
        id: HP:0001250
        label: Seizure
      onset:
        onset_category: INFANTILE
    evidence:
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
        explanation: >-
          This directly supports seizures in affected infants.
  - category: Developmental
    name: Psychomotor Delay
    description: Affected children have delayed psychomotor development before regression.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
      onset:
        onset_category: INFANTILE
    evidence:
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Early onset hypotonia, seizures and psychomotor delay were observed in both cases."
        explanation: >-
          Psychomotor delay in both reported cases supports global
          developmental delay.
  - category: Developmental
    name: Developmental Regression
    description: >-
      Progressive neurologic disease leads to loss of acquired motor and
      communication abilities in early childhood.
    phenotype_term:
      preferred_term: Developmental regression
      term:
        id: HP:0002376
        label: Developmental regression
      clinical_course: PROGRESSIVE
      onset:
        onset_category: INFANTILE
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "the natural history of the disease follows a fairly consistent pattern of infantile-onset hypotonia, seizures, delayed acquisition of early developmental milestones, followed by rapid developmental regression between 24 and 48 months of age."
        explanation: >-
          This directly supports early-childhood developmental regression after
          limited early skill acquisition.
  - category: Neurologic
    name: Leukodystrophy
    description: >-
      White-matter demyelination and leukodystrophy are central radiographic and
      pathological features.
    phenotype_term:
      preferred_term: Leukodystrophy
      term:
        id: HP:0002415
        label: Leukodystrophy
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:22508517
        reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination."
        explanation: >-
          This supports inflammatory demyelination as part of the ACOX1
          deficiency phenotype and mechanism.
  - category: Neurologic
    name: Cerebral and Cerebellar White Matter Abnormalities
    description: >-
      MRI can show cerebral and cerebellar white-matter abnormalities and
      progressive demyelinating lesions.
    phenotype_term:
      preferred_term: Abnormal cerebral white matter morphology
      term:
        id: HP:0002500
        label: Abnormal cerebral white matter morphology
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly indicative for a peroxisomal disorder."
        explanation: >-
          The case report directly describes cerebral and cerebellar white
          matter abnormalities.
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter."
        explanation: >-
          Serial MRI confirms progressive white-matter involvement.
  - category: Sensory
    name: Retinitis Pigmentosa
    frequency: FREQUENT
    description: Retinitis pigmentosa is reported as a common manifestation of ACOX1 deficiency.
    phenotype_term:
      preferred_term: Retinitis pigmentosa
      term:
        id: HP:0000510
        label: Rod-cone dystrophy
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
        explanation: >-
          This literature summary identifies retinitis pigmentosa as a common
          manifestation in reported ACOX1 deficiency.
    sequelae:
      - target: Visual Impairment
        description: Retinal degeneration contributes to visual impairment in the sensory branch of ACOX1 deficiency.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
            explanation: >-
              The clinical summary reports retinitis pigmentosa together with
              vision abnormalities, supporting a direct sensory sequela edge.
  - category: Sensory
    name: Visual Impairment
    frequency: FREQUENT
    description: Vision abnormalities and retinopathy can develop during the progressive course.
    phenotype_term:
      preferred_term: Visual impairment
      term:
        id: HP:0000505
        label: Visual impairment
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
        explanation: >-
          This supports visual impairment as a common manifestation in reported
          ACOX1 deficiency.
  - category: Sensory
    name: Hearing Impairment
    frequency: FREQUENT
    description: Hearing loss is reported during the neurodegenerative course.
    phenotype_term:
      preferred_term: Hearing impairment
      term:
        id: HP:0000365
        label: Hearing impairment
      clinical_course: PROGRESSIVE
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Retinitis pigmentosa, vision abnormalities, and hearing loss are also common manifestations"
        explanation: >-
          This supports hearing impairment as part of the reported phenotype
          spectrum.
  - category: Craniofacial
    name: Facial Dysmorphism
    frequency: OCCASIONAL
    description: Facial dysmorphism is a less frequently reported manifestation.
    phenotype_term:
      preferred_term: Facial dysmorphism
      term:
        id: HP:0001999
        label: Abnormal facial shape
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
        explanation: >-
          This literature summary reports facial dysmorphism as a less frequent
          finding in ACOX1 deficiency.
  - category: Hepatic
    name: Hepatic Dysfunction
    frequency: OCCASIONAL
    description: Hepatic dysfunction is a less frequently reported manifestation.
    phenotype_term:
      preferred_term: Hepatic dysfunction
      term:
        id: HP:0001410
        label: Decreased liver function
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
        explanation: >-
          This literature summary reports hepatic dysfunction as a less frequent
          finding; the HPO binding uses decreased liver function rather than
          hepatomegaly to match the quoted clinical statement.
  - category: Endocrine
    name: Adrenal Insufficiency
    frequency: OCCASIONAL
    description: Adrenal insufficiency is a less frequently reported manifestation.
    phenotype_term:
      preferred_term: Adrenal insufficiency
      term:
        id: HP:0000846
        label: Adrenal insufficiency
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "facial dysmorphism, hepatic dysfunction, and adrenal insufficiency are less frequently reported findings."
        explanation: >-
          This literature summary reports adrenal insufficiency as a less
          frequent finding in ACOX1 deficiency.
  - category: Neurologic
    name: Peripheral Neuropathy
    description: Peripheral neuropathy has been described in severe ACOX1 deficiency.
    phenotype_term:
      preferred_term: Peripheral neuropathy
      term:
        id: HP:0009830
        label: Peripheral neuropathy
    evidence:
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly indicative for a peroxisomal disorder."
        explanation: >-
          The fatal case report explicitly lists peripheral neuropathy among the
          clinical manifestations.
biochemical:
  - name: Elevated very-long-chain fatty acids
    presence: INCREASED
    readouts:
      - target: Very-Long-Chain Fatty Acid Accumulation
        relationship: READOUT_OF
        direction: POSITIVE
        endpoint_context: DIAGNOSTIC
        interpretation: >-
          Elevated VLCFA measurements are the diagnostic biochemical readout of
          the VLCFA accumulation node.
    biomarker_term:
      preferred_term: very long-chain fatty acid
      term:
        id: CHEBI:27283
        label: very long-chain fatty acid
    context: >-
      Increased plasma and cellular VLCFAs are the hallmark biochemical finding
      of ACOX1 deficiency, although plasma screening can be misleading in some
      cases.
    evidence:
      - reference: PMID:17458872
        reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The biochemical hallmark of this disorder is the accumulation of very long-chain fatty acids."
        explanation: >-
          This directly supports increased VLCFAs as the key biochemical
          abnormality.
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system."
        explanation: >-
          This supports elevated cellular VLCFAs and the isolated
          beta-oxidation defect.
  - name: Deficient C26:0 oxidation
    presence: DECREASED
    readouts:
      - target: ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency
        relationship: READOUT_OF
        direction: NEGATIVE
        endpoint_context: DIAGNOSTIC
        interpretation: >-
          Low C26:0 oxidation in fibroblasts reports the impaired ACOX1
          straight-chain acyl-CoA oxidase activity.
    biomarker_term:
      preferred_term: hexacosanoic acid
      term:
        id: CHEBI:31009
        label: hexacosanoic acid
    context: >-
      C26:0 oxidation activity is reduced in fibroblast testing, supporting an
      isolated peroxisomal beta-oxidation defect.
    evidence:
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system."
        explanation: >-
          This explicitly documents deficient C26:0 oxidation in patient
          fibroblasts.
  - name: Preserved phytanic acid, pristanic acid, and plasmalogen screening markers
    presence: NORMAL
    readouts:
      - target: ACOX1 Straight-Chain Acyl-CoA Oxidase Deficiency
        relationship: CORRELATES_WITH
        direction: THRESHOLD_DEPENDENT
        endpoint_context: DIAGNOSTIC
        interpretation: >-
          Normal phytanic acid, pristanic acid, and plasmalogen screening
          markers help distinguish isolated ACOX1 beta-oxidation deficiency
          from broader peroxisomal dysfunction but do not exclude disease.
    context: >-
      Normal phytanic acid, pristanic acid, and erythrocyte plasmalogen values
      can occur despite ACOX1 deficiency, creating a diagnostic pitfall.
    evidence:
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Plasma very-long-chain fatty acids were abnormal in both patients, whereas the plasma levels of phytanic acid, pristanic acid, the bile acid intermediates DHCA and THCA, and erythrocyte plasmalogen levels were normal."
        explanation: >-
          This supports preservation of other peroxisomal screening markers in
          isolated ACOX1 deficiency.
genetic:
  - name: ACOX1 pathogenic variants
    gene_term:
      preferred_term: ACOX1
      term:
        id: hgnc:119
        label: ACOX1
    association: Biallelic loss-of-function variants cause autosomal recessive ACOX1 deficiency.
    relationship_type: CAUSATIVE
    variant_origin: GERMLINE
    inheritance:
      - name: Autosomal recessive
        inheritance_term:
          preferred_term: Autosomal recessive inheritance
          term:
            id: HP:0000007
            label: Autosomal recessive inheritance
        evidence:
          - reference: PMID:17458872
            reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Peroxisomal acyl-coenzyme A (acyl-CoA) oxidase deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation due to a deficiency of straight-chain acyl-CoA oxidase (SCOX)."
            explanation: >-
              This directly supports autosomal recessive inheritance.
    variants:
      - name: ACOX1 intragenic deletion
        description: >-
          A homozygous deletion removing a large part of intron 3 and exons
          4-14 was reported in one patient.
        evidence:
          - reference: PMID:18536048
            reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Subsequent molecular analysis of ACOX1 showed a homozygous deletion, which removes a large part of intron 3 and exons 4-14 in the first patient."
            explanation: >-
              This documents a disease-causing ACOX1 deletion.
      - name: ACOX1 IVS3-1G>A splice-site variant
        description: >-
          A homozygous acceptor splice-site variant was identified in a fatal
          infantile case after fibroblast biochemical testing.
        evidence:
          - reference: PMID:16773508
            reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Enzymatic studies in these fibroblasts pointed to peroxisomal acyl-CoA oxidase deficiency and subsequent molecular analyses revealed a homozygous acceptor splice site mutation IVS3-1G>A in the ACOX1 gene (MIM *609751)."
            explanation: >-
              This directly supports the splice-site variant as a molecular
              diagnosis in ACOX1 deficiency.
    features: >-
      Published patients carry biallelic ACOX1 pathogenic variants, including
      deletions, missense changes, and splice/exon-skipping events. No clear
      genotype-phenotype correlation has been established.
    evidence:
      - reference: PMID:17458872
        reference_title: "Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "No clear genotype-phenotype correlation was observed."
        explanation: >-
          The cohort analysis supports limited genotype-phenotype correlation.
diagnosis:
  - name: Peroxisomal VLCFA and C26:0 oxidation testing
    description: >-
      Plasma VLCFA testing and fibroblast oxidation assays support diagnosis,
      but normal first-line plasma VLCFA values do not exclude ACOX1 deficiency.
    diagnosis_term:
      preferred_term: disease screening
      term:
        id: MAXO:0000124
        label: disease screening
    results: Elevated VLCFAs or deficient C26:0 oxidation support an isolated peroxisomal beta-oxidation defect.
    evidence:
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system."
        explanation: >-
          This supports fibroblast biochemical testing as a key diagnostic
          approach.
  - name: ACOX1 molecular genetic testing
    description: >-
      ACOX1 sequencing or deletion/splice analysis confirms the molecular
      diagnosis and distinguishes isolated ACOX1 deficiency from overlapping
      peroxisomal disorders.
    diagnosis_term:
      preferred_term: genetic testing
      term:
        id: MAXO:0000127
        label: genetic testing
    results: Biallelic pathogenic ACOX1 variants confirm peroxisomal acyl-CoA oxidase deficiency.
    evidence:
      - reference: PMID:18536048
        reference_title: "Peroxisomal acyl-CoA-oxidase deficiency: two new cases."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent molecular analysis of ACOX1 showed a homozygous deletion, which removes a large part of intron 3 and exons 4-14 in the first patient."
        explanation: >-
          This supports ACOX1 molecular analysis as confirmatory testing.
treatments:
  - name: Multidisciplinary Supportive Care
    description: >-
      Care is supportive and symptom-directed, including seizure management,
      developmental support, feeding and respiratory support, and surveillance
      for sensory and neurologic decline. No disease-modifying standard therapy
      is established.
    treatment_term:
      preferred_term: supportive care
      term:
        id: MAXO:0000950
        label: supportive care
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "Supportive care was initially recommended due to the degenerative natural history of the disorder."
        explanation: >-
          This supports supportive care as the default management approach, but
          does not establish a disease-modifying effect.
  - name: Hematopoietic Stem Cell Transplantation
    description: >-
      HSCT has been attempted in ACOX1 deficiency but did not halt the
      neurodegenerative course; available evidence suggests possible reduction
      of white-matter inflammation rather than disease arrest.
    treatment_term:
      preferred_term: hematopoietic stem cell transplantation
      term:
        id: MAXO:0000747
        label: hematopoietic stem cell transplantation
    target_mechanisms:
      - target: Neurodegenerative White Matter Disease
        treatment_effect: INHIBITS
        description: HSCT may reduce inflammatory white-matter disease but does not prevent progressive neurodegeneration.
        evidence:
          - reference: PMID:24619150
            reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
            supports: PARTIAL
            evidence_source: HUMAN_CLINICAL
            snippet: "Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain."
            explanation: >-
              This directly supports a partial anti-inflammatory effect without
              disease arrest.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain."
        explanation: >-
          HSCT evidence is limited and supports only partial modulation of
          brain inflammation.
differential_diagnoses:
  - name: Adrenoleukodystrophy
    disease_term:
      preferred_term: adrenoleukodystrophy
      term:
        id: MONDO:0018544
        label: adrenoleukodystrophy
    description: >-
      X-linked adrenoleukodystrophy overlaps through VLCFA accumulation,
      inflammatory CNS demyelination, and progressive neurologic decline, but is
      caused by ABCD1 transporter dysfunction rather than isolated ACOX1 enzyme
      deficiency.
    distinguishing_features:
      - >-
        ACOX1 deficiency shows deficient straight-chain acyl-CoA oxidase
        activity and ACOX1 variants; X-linked adrenoleukodystrophy is
        ABCD1-related.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Inherited deficiencies of peroxisomal straight chain VLCFA β-oxidation include only straight-chain acyl-CoA oxidase (ACOX1) deficiency (also known as “pseudo-neonatal ALD”) and X-linked adrenoleukodystrophy (X-ALD). These two disorders share symptoms and biochemical characteristics, with varying age of onset and velocity of disease progression."
        explanation: >-
          This directly supports X-ALD/adrenoleukodystrophy as a key overlapping
          differential diagnosis.
  - name: D-Bifunctional Protein Deficiency
    disease_term:
      preferred_term: d-bifunctional protein deficiency
      term:
        id: MONDO:0009855
        label: d-bifunctional protein deficiency
    description: >-
      D-bifunctional protein deficiency is another peroxisomal beta-oxidation
      disorder with overlapping neonatal hypotonia, seizures, liver involvement,
      VLCFA abnormalities, and severe neurodevelopmental disease.
    distinguishing_features:
      - >-
        ACOX1 deficiency affects the acyl-CoA oxidase step, whereas
        D-bifunctional protein deficiency is HSD17B4-related.
    evidence:
      - reference: PMID:24619150
        reference_title: "Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This is further supported by the progression of pyramidal tract degeneration from medullary to subcortical levels, and sequential loss of white matter proceeding from the dentate nuclei and superior cerebellar peduncles to involve the cerebellar white matter and remaining peduncles, and confirms the report of Suzuki et al and recent brain MRI data from N-ALD and bifunctional enzyme deficiency (Suzuki et al 2002; van der Knaap et al 2012)."
        explanation: >-
          This supports bifunctional enzyme deficiency as a related
          peroxisomal-disorder comparator in neuroimaging and white-matter
          progression.
  - name: Peroxisome Biogenesis Disorder
    disease_term:
      preferred_term: peroxisome biogenesis disorder
      term:
        id: MONDO:0019234
        label: peroxisome biogenesis disorder
    description: >-
      Peroxisome biogenesis disorders can present with overlapping neonatal
      neurologic disease and peroxisomal biochemical abnormalities, but involve
      broader peroxisome assembly defects rather than isolated ACOX1 deficiency.
    distinguishing_features:
      - >-
        Normal plasmalogen synthesis and normal phytanic/pristanic acid
        oxidation with deficient C26:0 oxidation favors isolated ACOX1
        beta-oxidation deficiency over a generalized peroxisome biogenesis
        disorder.
    evidence:
      - reference: PMID:16773508
        reference_title: "Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system."
        explanation: >-
          This supports biochemical differentiation of isolated beta-oxidation
          defects from broader peroxisomal biogenesis dysfunction.
experimental_models:
  - name: Patient fibroblast inflammatory response model
    description: >-
      Cultured patient fibroblasts model the ACOX1-deficient inflammatory
      response and demonstrate IL-1 pathway activation and cytokine modulation
      by MAPK, p38MAPK, and JNK inhibitors.
    experimental_model_type: PRIMARY_CELL_CULTURE
    organism:
      preferred_term: human
      term:
        id: NCBITaxon:9606
        label: Homo sapiens
    cell_types:
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
    cell_source: Patient-derived fibroblasts
    publication: PMID:22508517
    modeled_mechanisms:
      - target: Fibroblast IL-1 Cytokine Inflammatory Response
        description: Patient fibroblasts assay IL-1, IL-6, and IL-8 inflammatory signaling caused by ACOX1 deficiency.
    findings:
      - statement: IL-1 inflammatory pathway activation
      - statement: IL-6 and IL-8 cytokine secretion
      - statement: MAPK/p38MAPK/JNK inhibitor modulation
    evidence:
      - reference: PMID:22508517
        reference_title: "The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy)."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors."
        explanation: >-
          This supports patient fibroblasts as a model of ACOX1-deficient
          inflammatory signaling and pharmacologic modulation.
  - name: Acox1-deficient BV-2 microglial cell model
    description: >-
      Mutant BV-2 microglial cell lines model peroxisomal beta-oxidation
      defects, VLCFA accumulation, lipid/immune/autophagy reprogramming, and a
      disease-associated microglial signature.
    experimental_model_type: CELL_LINE
    cell_types:
      - preferred_term: microglial cell
        term:
          id: CL:0000129
          label: microglial cell
    cell_source: BV-2 microglial cell line
    publication: PMID:37138705
    modeled_mechanisms:
      - target: Microglial Disease-Associated Inflammatory Phenotype
        description: Mutant microglia model lipid, immune, autophagy, and DAM-like programs.
    findings:
      - statement: VLCFA accumulation
      - statement: DAM-like transcriptional signature
      - statement: cholesterol accumulation in plasma membranes
      - statement: altered autophagy patterns
    evidence:
      - reference: PMID:37138705
        reference_title: "Peroxisomal defects in microglial cells induce a disease-associated microglial signature."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation."
        explanation: >-
          This supports the BV-2 mutant microglial model as relevant to
          peroxisomal beta-oxidation defects including Acox1 loss.
notes: >-
  Falcon surfaced NCT01668186 and NCT02171104 as broad peroxisomal/metabolic
  disorder studies, but they were not modeled as ACOX1-deficiency clinical
  trials because the cached trial summaries are not specific to MONDO:0009919.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 36 citations 2026-05-10T16:27:36.161409

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Peroxisomal Acyl-CoA Oxidase Deficiency
  • MONDO ID: (if available)
  • Category: Metabolic Disorder

Research Objectives

Please provide a comprehensive research report on Peroxisomal Acyl-CoA Oxidase Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

10. Diagnostics

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

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

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

11. Outcome/Prognosis

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

12. Treatment

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

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

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

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

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

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

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

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

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

    Search first: VBO (Vertebrate Breed Ontology)

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

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Comprehensive Research Report: Peroxisomal Acyl‑CoA Oxidase Deficiency (ACOX1 deficiency)

Executive summary

Peroxisomal acyl‑CoA oxidase deficiency is a rare autosomal recessive peroxisomal fatty‑acid β‑oxidation disorder caused by biallelic pathogenic variants in ACOX1, leading to impaired oxidation of straight‑chain very‑long‑chain fatty acids (VLCFAs) and typically elevated plasma C26:0 (cerotic acid). It presents most often in infancy with hypotonia, seizures, severe developmental delay and progressive leukodystrophy with regression, often fatal in childhood, although later-onset presentations are described. Recent (2023–2024) research has emphasized innate-immune and microglial contributions (disease-associated microglia signatures, lysosome/autophagy programs) and has highlighted newborn-screening-relevant lipid biomarkers for early detection of peroxisomal disorders. (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, wanders2021fattyacidoxidation pages 69-70, mohan2023evaluatingthestrength pages 3-4, raas2023peroxisomaldefectsin pages 1-2)

1. Disease information

1.1 What is the disease?

Definition (current understanding): Peroxisomal acyl‑CoA oxidase deficiency (often called pseudoneonatal adrenoleukodystrophy, “pseudo‑NALD”, or “pseudo‑neonatal ALD”) is an inborn error of metabolism due to deficiency of straight‑chain acyl‑CoA oxidase (ACOX1), the first enzyme in peroxisomal β‑oxidation of straight‑chain VLCFAs. The core biochemical hallmark is impaired peroxisomal β‑oxidation with accumulation of VLCFAs, particularly C26:0 in plasma. (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, rosewich12006pitfallinmetabolic pages 1-2)

A mechanistically explicit statement from a primary functional paper: pseudoneonatal adrenoleukodystrophy is characterized by ACOX1 deficiency leading to “accumulation of very‑long‑chain fatty acids (VLCFA) and inflammatory demyelination.” (hajj2012theinflammatoryresponse pages 1-1)

1.2 Key identifiers (as retrieved in the available corpus)

  • OMIM disease: #264470 (pseudoneonatal adrenoleukodystrophy / ACOX1 deficiency) (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, hajj2012theinflammatoryresponse pages 1-1)
  • Causal gene: ACOX1 (straight‑chain acyl‑CoA oxidase 1) (ferdinandusse2007clinicalbiochemicaland pages 1-2)
  • OMIM gene: ACOX1 *609751 (rosewich12006pitfallinmetabolic pages 1-2, ferdinandusse2007clinicalbiochemicaland pages 1-2)

Not retrieved in this tool run: MONDO ID, Orphanet ID, ICD‑10/ICD‑11 codes, MeSH term for the specific disease entity. These should be added from external curated resources (e.g., OMIM/Orphanet/MONDO browsers) but were not present in the retrieved full-text corpus.

1.3 Synonyms / alternative names

  • Pseudoneonatal adrenoleukodystrophy (P‑NALD) (ferdinandusse2007clinicalbiochemicaland pages 1-2, hajj2012theinflammatoryresponse pages 1-1)
  • Pseudo‑neonatal ALD (wang2014effectsofhematopoietic pages 1-2, rosewich12006pitfallinmetabolic pages 1-2)

1.4 Evidence source type

The compiled information is primarily derived from: - Aggregated disease-level resources via primary cohorts/reviews (e.g., Human Mutation 2007 cohort; later synthesis) (ferdinandusse2007clinicalbiochemicaland pages 1-2, wanders2021fattyacidoxidation pages 69-70) - Individual patient case reports (e.g., Neuropediatrics 2006; Am J Med Genet A 2008) (rosewich12006pitfallinmetabolic pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2) - Experimental disease models (in vitro microglia/fibroblasts) informing mechanism (hajj2012theinflammatoryresponse pages 1-1, raas2023peroxisomaldefectsin pages 1-2)

Artifact: identifiers & nomenclature

Identifier type Value Notes Source
Disease name Peroxisomal acyl-CoA oxidase deficiency Rare single-enzyme peroxisomal disorder caused by deficiency of straight-chain acyl-CoA oxidase/ACOX1; core biochemical defect is impaired peroxisomal β-oxidation with VLCFA accumulation, especially C26:0; autosomal recessive (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2) Ferdinandusse et al., 2007, Human Mutation, https://doi.org/10.1002/humu.20535; Carrozzo et al., 2008, Am J Med Genet A, https://doi.org/10.1002/ajmg.a.32298
OMIM disease ID OMIM #264470 Disease entry for ACOX1 deficiency; also cited for pseudoneonatal adrenoleukodystrophy/P-NALD (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, hajj2012theinflammatoryresponse pages 1-1) Carrozzo et al., 2008, https://doi.org/10.1002/ajmg.a.32298; Hajj et al., 2012, https://doi.org/10.1210/en.2012-1137
Gene symbol ACOX1 Encodes peroxisomal acyl-CoA oxidase 1 / straight-chain acyl-CoA oxidase, the first enzyme in peroxisomal VLCFA β-oxidation (ferdinandusse2007clinicalbiochemicaland pages 1-2, wanders2021fattyacidoxidation pages 69-70) Ferdinandusse et al., 2007, https://doi.org/10.1002/humu.20535; Wanders et al., 2021, https://doi.org/10.1007/978-3-030-60204-8_5
Gene MIM MIM *609751 Gene identifier for ACOX1; molecular testing of ACOX1 confirms diagnosis (rosewich12006pitfallinmetabolic pages 1-2, ferdinandusse2007clinicalbiochemicaland pages 1-2) Rosewich et al., 2006, https://doi.org/10.1055/s-2006-923943; Ferdinandusse et al., 2007, https://doi.org/10.1002/humu.20535
Historical synonym Pseudoneonatal adrenoleukodystrophy Historical/alternative name widely used in literature for ACOX1 deficiency (ferdinandusse2007clinicalbiochemicaland pages 1-2, hajj2012theinflammatoryresponse pages 1-2) Ferdinandusse et al., 2007, https://doi.org/10.1002/humu.20535; Hajj et al., 2012, https://doi.org/10.1210/en.2012-1137
Alternate synonym P-NALD / pseudo-neonatal ALD Abbreviated synonym used in case reports and reviews; reflects phenotypic overlap with neonatal ALD but due to isolated ACOX1 deficiency (wang2014effectsofhematopoietic pages 1-2, rosewich12006pitfallinmetabolic pages 1-2) Wang et al., 2014, https://doi.org/10.1007/s10545-014-9698-3; Rosewich et al., 2006, https://doi.org/10.1055/s-2006-923943
Disease class Peroxisomal β-oxidation defect Specifically a defect of straight-chain very-long-chain fatty acid β-oxidation in peroxisomes (wang2014effectsofhematopoietic pages 1-2, rosewich12006pitfallinmetabolic pages 1-2) Wang et al., 2014, https://doi.org/10.1007/s10545-014-9698-3; Rosewich et al., 2006, https://doi.org/10.1055/s-2006-923943
Hallmark biochemical marker Elevated plasma VLCFAs, especially C26:0; increased C26:0/C22:0 ratio Plasma VLCFA abnormality is the key biochemical signature; phytanic/pristanic acids and plasmalogens may be normal in some patients (rosewich12006pitfallinmetabolic pages 3-4, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2) Rosewich et al., 2006, https://doi.org/10.1055/s-2006-923943; Carrozzo et al., 2008, https://doi.org/10.1002/ajmg.a.32298
Inheritance Autosomal recessive Confirmed in clinical series and case reports; affected individuals typically carry biallelic pathogenic ACOX1 variants (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2) Ferdinandusse et al., 2007, https://doi.org/10.1002/humu.20535; Carrozzo et al., 2008, https://doi.org/10.1002/ajmg.a.32298

Table: This table summarizes the principal names, identifiers, and defining biochemical/genetic features of peroxisomal acyl-CoA oxidase deficiency. It is useful for harmonizing disease nomenclature and core database fields for knowledge-base curation.

2. Etiology

2.1 Disease causal factors

  • Primary cause: biallelic pathogenic variants in ACOX1 causing loss of ACOX1 enzyme activity and impaired peroxisomal straight‑chain VLCFA β‑oxidation. (ferdinandusse2007clinicalbiochemicaland pages 1-2, rosewich12006pitfallinmetabolic pages 1-2)
  • Mechanistic consequence: VLCFA accumulation and downstream inflammatory demyelination (hajj2012theinflammatoryresponse pages 1-1)

2.2 Risk factors

  • Genetic: autosomal recessive inheritance; affected individuals typically have biallelic pathogenic ACOX1 variants (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2). In a fatal case with misleading screening results, parental heterozygosity was shown for an ACOX1 splice variant, consistent with recessive inheritance. (rosewich12006pitfallinmetabolic pages 3-4)
  • Environmental: no specific environmental risk factors or triggers are established in the retrieved ACOX1-deficiency literature.

2.3 Protective factors

No validated genetic or environmental protective factors were identified in the retrieved corpus for ACOX1 deficiency.

2.4 Gene–environment interactions

No ACOX1-deficiency–specific gene–environment interactions were identified in the retrieved corpus.

3. Phenotypes

3.1 Phenotypic spectrum (signs/symptoms/lab)

A 2021 synthesis of reported cases describes classic features including hypotonia, seizures, visual system failure, impaired hearing, facial dysmorphism, hepatomegaly, and failure to thrive, along with cerebral and/or cerebellar white matter abnormalities on neuroimaging. (wanders2021fattyacidoxidation pages 69-70)

A primary mechanistic/clinical description in Endocrinology summarizes P‑NALD as “characterized by craniofacial dysmorphia, generalized hypotonia, hepatomegaly, infantile seizures, loss of motor achievements, and white matter demyelination.” (hajj2012theinflammatoryresponse pages 1-2)

3.2 Age of onset, severity, progression, and frequency

  • Typical onset: neonatal/infantile hypotonia and infantile seizures are repeatedly reported. (ferdinandusse2007clinicalbiochemicaland pages 1-2, rosewich12006pitfallinmetabolic pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)
  • Progression/regression: a review summarizing a 26‑patient series states most patients acquire limited skills but 83% showed loss of motor achievements with mean age of regression 28 months. (wanders2021fattyacidoxidation pages 69-70)
  • Mortality/prognosis: the same synthesis reports a mean age of death of 5 years (range 4–10) in that cohort, while acknowledging rare adult-onset cases. (wanders2021fattyacidoxidation pages 69-70)

3.3 Quality of life impact

Formal QoL instruments (EQ‑5D/SF‑36/PROMIS) were not identified in the retrieved corpus. However, the reported course—developmental regression with loss of vision/hearing and motor function—implies profound impairment of daily functioning and caregiver burden. (wang2014effectsofhematopoietic pages 1-2, wanders2021fattyacidoxidation pages 69-70)

3.4 Suggested HPO mapping

Phenotype (plain language) Suggested HPO term(s) and ID(s) Typical onset/course Frequency/statistics (if stated) Evidence/source with year+URL
Neonatal/infantile hypotonia Hypotonia (HP:0001252); Neonatal hypotonia (HP:0001290) Usually neonatal or early infancy; often progressive as part of neurodegenerative course Reported repeatedly in severe early-onset cases; no pooled % given in available evidence Ferdinandusse et al. 2007, https://doi.org/10.1002/humu.20535; Carrozzo et al. 2008, https://doi.org/10.1002/ajmg.a.32298; Wang et al. 2014, https://doi.org/10.1007/s10545-014-9698-3 (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, wang2014effectsofhematopoietic pages 1-2)
Infantile seizures Seizure (HP:0001250); Infantile spasms/epileptic seizures if specified clinically (HP:0012469 / HP:0002123, suggestive) Infancy; often early and associated with severe neurologic disease Common in case reports/series; no pooled % stated in available excerpts Ferdinandusse et al. 2007, https://doi.org/10.1002/humu.20535; Carrozzo et al. 2008, https://doi.org/10.1002/ajmg.a.32298; Rosewich et al. 2006, https://doi.org/10.1055/s-2006-923943 (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, rosewich12006pitfallinmetabolic pages 1-2)
Psychomotor retardation / global developmental delay Global developmental delay (HP:0001263); Psychomotor retardation (HP:0001263, common mapping); Intellectual disability, profound/severe if later confirmed (HP:0010864/HP:0010864 family, suggestive) Infancy to early childhood; severe delay with limited skill acquisition In a 26-patient series, all had psychomotor retardation Wanders et al. 2021 review summarizing clinical series, https://doi.org/10.1007/978-3-030-60204-8_5; Ferdinandusse et al. 2007, https://doi.org/10.1002/humu.20535 (wanders2021fattyacidoxidation pages 69-70, ferdinandusse2007clinicalbiochemicaland pages 1-2)
Regression / loss of motor achievements Neurodevelopmental regression (HP:0002376); Loss of ambulation (HP:0002505, if applicable); Motor regression (suggestive mapping under regression) Typically early childhood after limited development; progressive decline In the 26-patient cohort, 83% lost motor achievements; mean age of regression 28 months Wanders et al. 2021 review summarizing 2007 cohort, https://doi.org/10.1007/978-3-030-60204-8_5 (wanders2021fattyacidoxidation pages 69-70)
Leukodystrophy / white matter demyelination (cerebral/cerebellar) Leukodystrophy (HP:0002415); Abnormal cerebral white matter morphology (HP:0002500); Demyelination of the cerebral white matter (HP:0007256); Cerebellar white matter abnormality (suggestive) Usually progressive from infancy/early childhood; MRI shows cerebral and/or cerebellar white matter involvement Cerebral and/or cerebellar white matter abnormalities described in series; no pooled % stated in available excerpts Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5; Rosewich et al. 2006, https://doi.org/10.1055/s-2006-923943; Wang et al. 2014, https://doi.org/10.1007/s10545-014-9698-3 (wanders2021fattyacidoxidation pages 69-70, rosewich12006pitfallinmetabolic pages 1-2, wang2014effectsofhematopoietic pages 1-2)
Vision loss / retinopathy Visual impairment (HP:0000505); Blindness (HP:0000618); Retinal dystrophy/retinopathy (HP:0000556 / HP:0000488, suggestive depending on exam) Progressive; may accompany regression and advanced neurodegeneration Vision failure/loss described in cohort and case reports; no pooled % stated in available excerpts Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5; Rosewich et al. 2006, https://doi.org/10.1055/s-2006-923943; Wang et al. 2014, https://doi.org/10.1007/s10545-014-9698-3 (wanders2021fattyacidoxidation pages 69-70, rosewich12006pitfallinmetabolic pages 1-2, wang2014effectsofhematopoietic pages 1-2)
Hearing impairment / deafness Hearing impairment (HP:0000365); Sensorineural hearing impairment (HP:0000407); Deafness (HP:000036 deafness family, suggestive) Progressive in some patients; may occur with global neurologic decline Hearing impairment noted in series and case reports; no pooled % stated in available excerpts Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5; Rosewich et al. 2006, https://doi.org/10.1055/s-2006-923943; Wang et al. 2014, https://doi.org/10.1007/s10545-014-9698-3 (wanders2021fattyacidoxidation pages 69-70, rosewich12006pitfallinmetabolic pages 1-2, wang2014effectsofhematopoietic pages 1-2)
Hepatomegaly Hepatomegaly (HP:0002240) Infantile or early childhood; may coexist with liver enzyme abnormalities Mentioned as a characteristic feature; no % stated in available excerpts Hajj et al. 2012, https://doi.org/10.1210/en.2012-1137; Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5 (hajj2012theinflammatoryresponse pages 1-2, wanders2021fattyacidoxidation pages 69-70)
Failure to thrive / poor feeding Failure to thrive (HP:0001508); Poor feeding (HP:0011968) Neonatal/infantile; may precede or accompany hypotonia and seizures Described in early-onset severe cases; no pooled % stated in available excerpts Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5; Rosewich et al. 2006, https://doi.org/10.1055/s-2006-923943 (wanders2021fattyacidoxidation pages 69-70, rosewich12006pitfallinmetabolic pages 1-2)
Craniofacial dysmorphism Facial dysmorphism (HP:0001999); Abnormality of the face (HP:0000271) Congenital/early recognized; generally non-remitting Mentioned as characteristic in pseudoneonatal adrenoleukodystrophy; no % stated Hajj et al. 2012, https://doi.org/10.1210/en.2012-1137; Wanders et al. 2021, https://doi.org/10.1007/978-3-030-60204-8_5 (hajj2012theinflammatoryresponse pages 1-2, wanders2021fattyacidoxidation pages 69-70)
Adrenal dysfunction / elevated ACTH Adrenal insufficiency (HP:0000846); Increased circulating ACTH level (HP:0030831, suggestive) Can emerge during childhood in some cases; endocrine monitoring may be warranted Reported in at least one case with elevated ACTH; frequency not established in available evidence Carrozzo et al. 2008, https://doi.org/10.1002/ajmg.a.32298 (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)

Table: This table maps major reported clinical features of peroxisomal acyl-CoA oxidase deficiency to suggested HPO terms and summarizes onset, progression, and any available frequency data. It is useful for structured disease curation and phenotype annotation in a knowledge base.

4. Genetic / molecular information

4.1 Causal gene(s)

  • ACOX1 encodes peroxisomal acyl‑CoA oxidase 1 (straight‑chain acyl‑CoA oxidase), a key enzyme initiating peroxisomal β‑oxidation of straight‑chain VLCFA‑CoA substrates. (wanders2021fattyacidoxidation pages 69-70, ferdinandusse2007clinicalbiochemicaland pages 1-2)

A mechanistic note from patient-based work: ACOX1 “is encoded by a single gene, which generates two splice variants,” producing two isoforms; the disorder reflects loss of enzyme function. (hajj2012theinflammatoryresponse pages 1-2)

4.2 Pathogenic variants (examples; not exhaustive)

Variant-level evidence in the retrieved corpus includes: - A homozygous splice-site variant IVS3‑1G>A causing exon skipping (fatal infant case; parents heterozygous). (rosewich12006pitfallinmetabolic pages 3-4) - Large deletions and point mutations/exon-skipping variants have been reported in patients in general, consistent with loss-of-function mechanisms. (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)

Variant frequencies (gnomAD/ExAC) and ACMG classifications were not available in the retrieved corpus and should be added from ClinVar/gnomAD in a subsequent curation pass.

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities specific to ACOX1 deficiency were identified in the retrieved corpus.

5. Environmental information

No validated environmental, lifestyle, or infectious contributors specific to ACOX1 deficiency were identified in the retrieved corpus.

6. Mechanism / pathophysiology

6.1 Causal chain (upstream → downstream)

1) ACOX1 loss-of-function → 2) impaired peroxisomal straight‑chain VLCFA β‑oxidation → 3) VLCFA accumulation in plasma/tissues → 4) cellular stress and inflammatory signaling (including IL‑1 axis) → 5) inflammatory demyelination / leukodystrophy and neurodegeneration. (hajj2012theinflammatoryresponse pages 1-1, rosewich12006pitfallinmetabolic pages 1-2, wanders2021fattyacidoxidation pages 69-70)

6.2 Inflammation and signaling (human fibroblast evidence)

Endocrinology 2012 used transcriptomic profiling of patient fibroblasts and concluded: “the absence of acyl‑coenzyme A oxidase 1 activity in P‑NALD fibroblasts triggers an inflammatory process, in which the IL‑1 pathway seems to be central.” They also report IL‑6/IL‑8 downregulation by kinase inhibitors: “expression of IL‑6 and IL‑8 cytokines in patient fibroblasts was down‑regulated by MAPK, p38MAPK, and Jun N‑terminal kinase inhibitors,” motivating inflammation-modulating strategies as a mechanistic hypothesis (preclinical/in vitro). (hajj2012theinflammatoryresponse pages 1-2)

Suggested GO biological process terms (examples): - Peroxisomal fatty acid beta-oxidation (GO:0006635) - Inflammatory response (GO:0006954) - Interleukin-1–mediated signaling pathway (GO:0070498) - Cytokine-mediated signaling pathway (GO:0019221)

6.3 Microglia-centered mechanisms (2023 development)

A 2023 BV‑2 microglia RNA‑seq study modeling peroxisomal β‑oxidation defects (including Acox1−/−) found large-scale transcriptional changes including lipid metabolism and immune programs and described “a DAM-like signature,” along with “cholesterol accumulation in plasma membranes” and altered lysosome/autophagy programs. The authors conclude peroxisomal defects in microglia “force microglial cells to adopt a pathological phenotype” likely contributing to peroxisomal leukodystrophy pathogenesis. (raas2023peroxisomaldefectsin pages 1-2)

Suggested CL (cell ontology) term: microglial cell (CL:0000129)

Suggested GO terms (examples): - Microglial cell activation (GO:0001774) - Autophagy (GO:0006914) - Lysosome organization (GO:0007040) - Cholesterol homeostasis (GO:0042632)

6.4 Biochemical abnormalities and metabolites (CHEBI suggestions)

  • Very long-chain fatty acids (group) (rosewich12006pitfallinmetabolic pages 1-2)
  • Cerotic acid (C26:0) (CHEBI:28841) (C26:0 highlighted as marker in patient testing) (rosewich12006pitfallinmetabolic pages 3-4)
  • C26:0‑lysophosphatidylcholine (C26:0‑LPC; used in NBS for related peroxisomal disorders) (mohan2023evaluatingthestrength pages 3-4)

6.5 Tissue/cell injury and anatomical correlates

The dominant clinical pathology is CNS white matter involvement (leukodystrophy/demyelination) with additional systemic involvement such as hepatomegaly in some cases. (wanders2021fattyacidoxidation pages 69-70, hajj2012theinflammatoryresponse pages 1-2)

Suggested UBERON terms (examples): - Brain white matter (UBERON:0002317) - Cerebellum (UBERON:0002037) - Liver (UBERON:0002107)

6.6 Molecular profiling / omics

  • Patient-fibroblast transcriptomics and inflammatory pathway profiling were used to identify IL‑1 pathway activation. (hajj2012theinflammatoryresponse pages 1-2)
  • Microglial RNA‑seq defined immune/lipid/autophagy modules and DAM-like programs under peroxisomal defects. (raas2023peroxisomaldefectsin pages 1-2)

7. Anatomical structures affected

7.1 Organ-level involvement

  • Central nervous system: cerebral and cerebellar white matter abnormalities / demyelination (wanders2021fattyacidoxidation pages 69-70, rosewich12006pitfallinmetabolic pages 1-2)
  • Liver: hepatomegaly described in clinical phenotypes (hajj2012theinflammatoryresponse pages 1-2, wanders2021fattyacidoxidation pages 69-70)
  • Auditory and visual systems: progressive hearing and visual impairment reported (wanders2021fattyacidoxidation pages 69-70, wang2014effectsofhematopoietic pages 1-2)

7.2 Tissue/cell-level targets

  • Oligodendrocyte–myelin units are implied targets by leukodystrophy/demyelination phenotype. (wanders2021fattyacidoxidation pages 69-70)
  • Microglia are implicated mechanistically by disease-associated transcriptional changes under peroxisomal β‑oxidation impairment. (raas2023peroxisomaldefectsin pages 1-2)

7.3 Subcellular localization (GO cellular component)

  • Peroxisome (GO:0005777) is the primary subcellular compartment for the enzymatic defect.

8. Temporal development

8.1 Onset

Most reported cases present in the neonatal period or infancy with hypotonia and seizures. (ferdinandusse2007clinicalbiochemicaland pages 1-2, rosewich12006pitfallinmetabolic pages 1-2)

8.2 Progression

The disease course is typically progressive neurodegeneration with regression in early childhood; in a summarized cohort, regression occurred at mean 28 months. (wanders2021fattyacidoxidation pages 69-70)

8.3 Remission/critical windows

No validated remission patterns were identified. The early childhood period before regression would be the presumed critical window for any future disease-modifying therapy, based on natural history summaries. (wanders2021fattyacidoxidation pages 69-70)

9. Inheritance and population

9.1 Inheritance

  • Autosomal recessive (ferdinandusse2007clinicalbiochemicaland pages 1-2, carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)

9.2 Epidemiology

Population-level prevalence and incidence values were not identified in the retrieved corpus. Available evidence indicates extreme rarity: one report notes that only a small number of patients (~22 worldwide) had been reported at the time of publication. (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)

10. Diagnostics

10.1 Core laboratory findings (clinical biochemistry)

  • Typical diagnostic biochemical signature: elevated VLCFAs, including increased C26:0 and increased C26:0/C22:0 ratio. (rosewich12006pitfallinmetabolic pages 3-4)
  • Some patients may have normal phytanic and pristanic acid oxidation and normal plasmalogen synthesis in fibroblasts, consistent with an isolated straight-chain VLCFA β‑oxidation defect. (rosewich12006pitfallinmetabolic pages 1-2)

Diagnostic pitfall: A fatal case report emphasizes that “the finding of a normal very long-chain fatty acid profile does not exclude a peroxisomal disorder,” supporting reflex testing beyond plasma VLCFA in clinically suggestive cases. (rosewich12006pitfallinmetabolic pages 1-2)

10.2 Confirmatory testing

  • Fibroblast functional testing: markedly decreased C26:0 oxidation and reduced ACOX1 enzyme activity in cultured fibroblasts; immunoblot patterns can support ACOX1 deficiency. (rosewich12006pitfallinmetabolic pages 3-4)
  • Molecular genetic testing: ACOX1 sequencing / transcript analysis confirms diagnosis (ferdinandusse2007clinicalbiochemicaland pages 1-2, rosewich12006pitfallinmetabolic pages 1-2). A review statement: “definitive diagnosis of patients requires enzyme analysis in fibroblasts and/or genetic analysis of the ACOX1 gene.” (wanders2021fattyacidoxidation pages 69-70)

10.3 Newborn screening and early detection (context and real-world implementation)

While ACOX1 deficiency is not a standard standalone newborn screening target in most jurisdictions, peroxisomal disorder newborn screening (initiated for X‑ALD) can detect broader classes of peroxisomal disorders. The ClinGen peroxisomal curation/nomenclature paper emphasizes: “Newborn screening identifying elevated C26:0-lysophosphatidyl choline (C26:0-LPC) and molecular genetic testing are critical tools for the early detection of peroxisomal disorders.” (mohan2023evaluatingthestrength pages 3-4)

10.4 Differential diagnosis (high-level)

Given overlapping biochemical and neuroimaging phenotypes, important differentials include other peroxisomal disorders with VLCFA elevation (e.g., X‑ALD, D-bifunctional protein deficiency, peroxisome biogenesis disorders). The diagnostic pitfall literature supports performing fibroblast enzymology/genetics when first-line plasma testing is non-diagnostic despite suggestive clinical features. (rosewich12006pitfallinmetabolic pages 1-2)

11. Outcome / prognosis

  • Severe childhood phenotype is common and frequently fatal in childhood (mean death age 5 years; range 4–10 in a summarized cohort). (wanders2021fattyacidoxidation pages 69-70)
  • Rare later-onset adult presentations exist. (wanders2021fattyacidoxidation pages 69-70)

Prognostic biomarkers beyond VLCFA levels were not identified in the retrieved corpus.

12. Treatment

12.1 Supportive care (standard of care)

The retrieved corpus did not provide formal consensus guidelines for ACOX1 deficiency. In practice, care is typically supportive and multidisciplinary (seizure management, nutritional support, management of feeding difficulties, respiratory/infection prevention), consistent with severe neurodegenerative leukodystrophy phenotypes. (inferred from described phenotypic course; see clinical cases) (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2, wang2014effectsofhematopoietic pages 1-2)

Suggested MAXO terms (examples): - Antiseizure therapy (MAXO:0000754; generic class) - Nutritional support therapy (MAXO:0000076) - Physical therapy/rehabilitation (MAXO:0000015)

12.2 Hematopoietic stem cell transplantation (HSCT) – limited evidence

A sibling comparison study evaluated HSCT in ACOX1 deficiency and reported: “Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain.” (wang2014effectsofhematopoietic pages 1-2)

Interpretation: HSCT may modulate neuroinflammation but is not established as disease-modifying for the neurodegenerative course; evidence is limited to small numbers and should be considered investigational/high-risk.

Suggested MAXO term: Hematopoietic stem cell transplantation (MAXO:0000747)

12.3 Mechanism-motivated anti-inflammatory strategies (preclinical/in vitro)

Patient fibroblast studies suggest kinase inhibitors can down-modulate inflammatory cytokine expression, and authors propose: “The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status.” (hajj2012theinflammatoryresponse pages 1-2)

This is not clinical efficacy evidence; it provides a hypothesis linking VLCFA accumulation to cytokine networks and identifies candidate signaling nodes (MAPK/p38/JNK) for translational exploration.

12.4 Clinical trials / studies (real-world implementation)

  • NCT01668186 (Recruiting; observational): Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD). URL: https://clinicaltrials.gov/study/NCT01668186. (ClinicalTrials.gov record retrieved in this run; peroxisomal disorders broadly)
  • NCT02171104 (Active, not recruiting; Phase 2): MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis. URL: https://clinicaltrials.gov/study/NCT02171104. (Trial includes metabolic disorders broadly)

These studies provide infrastructure for peroxisomal disorder natural history and transplant protocols but are not necessarily ACOX1-deficiency–specific.

13. Prevention

Given autosomal recessive inheritance, prevention focuses on genetic counseling and reproductive options: - Carrier testing for at-risk relatives once familial ACOX1 variants are known. (rosewich12006pitfallinmetabolic pages 3-4) - Prenatal or preimplantation genetic testing is feasible in principle when pathogenic variants are identified (general principles supported by the existence of prenatal diagnostic approaches for fatty acid oxidation/peroxisomal disorders). (wanders2021fattyacidoxidation pages 69-70)

Primary prevention via lifestyle/environmental modifications is not established.

14. Other species / natural disease

The retrieved corpus did not contain a clear naturally occurring veterinary disease homolog explicitly attributed to ACOX1 loss-of-function.

15. Model organisms

15.1 Mouse models (ACOX1 loss)

A classic Acox1 knockout mouse study (biochemical and hepatic phenotype) reports that ACOX-null mice “accumulate very long chain fatty acids in blood” and display liver pathology and altered peroxisome biology, demonstrating systemic consequences of ACOX loss. (fan1996 was retrieved but not processed into a citeable evidence snippet in this run; therefore not cited here.)

15.2 Cellular models (microglia)

A 2023 BV‑2 Acox1−/− microglial model recapitulated VLCFA accumulation and revealed DAM-like immune signatures, lysosome/autophagy programs, and cholesterol membrane changes, providing a mechanistic bridge to neuroinflammatory leukodystrophy. (raas2023peroxisomaldefectsin pages 1-2)

15.3 Zebrafish model (ACOX1 gain-of-function; adjacent ACOX1 biology)

A 2024 zebrafish model was developed for ACOX1 gain-of-function Mitchell syndrome (distinct from recessive ACOX1 deficiency) to study leukodystrophy mechanisms and test microglia-targeted antioxidant approaches; this supports broader ACOX1–white matter–neuroinflammation links but is not a direct loss-of-function model for OMIM #264470. (Not extracted into evidence snippets in this run; not cited.)

2023–2024 “latest research” highlights (prioritized)

1) ClinGen/curation and nomenclature: Mohan et al. (May 2023, Molecular Genetics and Metabolism) describes the ClinGen Peroxisomal Gene Curation Expert Panel and notes that ACOX1 was curated for two different disease entities (loss-of-function vs upregulation/gain-of-function), and that newborn screening and molecular testing are critical tools for early detection of peroxisomal disorders. URL: https://doi.org/10.2139/ssrn.4330003 (mohan2023evaluatingthestrength pages 3-4)

2) Microglial disease programs under peroxisomal β‑oxidation impairment: Raas et al. (Apr 2023, Frontiers in Molecular Neuroscience) demonstrates that peroxisomal defects (including Acox1−/−) induce microglial immune reprogramming with “a DAM-like signature,” implicating microglia and autophagy/lysosomal processes as mechanistic contributors and potential therapeutic targets. URL: https://doi.org/10.3389/fnmol.2023.1170313 (raas2023peroxisomaldefectsin pages 1-2)

3) Peroxisomes and neuroinflammation (broader context): Sarkar & Lipinski (Oct 2024, Cells) reviews that peroxisomal functions (VLCFA degradation, ether lipid synthesis, ROS metabolism) are essential for restricting neuroinflammation and suggests strategies to enhance peroxisome biogenesis as a possible anti-inflammatory approach in the CNS. URL: https://doi.org/10.3390/cells13191655 (sarkar2024roleandfunction pages 9-10)

Key data/statistics extracted

  • Regression/loss of motor achievements in 83% of patients; mean age of regression 28 months (summary of a 26‑patient series). (wanders2021fattyacidoxidation pages 69-70)
  • Mean age of death 5 years (range 4–10) in that summarized cohort. (wanders2021fattyacidoxidation pages 69-70)
  • Case-report enzymology example: ACOX1 activity ~10% of normal in fibroblasts (9.8 vs 89 pmol/min·mg) (rosewich12006pitfallinmetabolic pages 3-4)

Limitations / gaps for knowledge-base completion

  • MONDO/Orphanet/ICD/MeSH identifiers were not recovered in the retrieved full texts.
  • Robust prevalence/incidence estimates are absent in the retrieved corpus.
  • Variant-level population frequencies and ClinVar classifications were not retrieved.
  • Evidence for disease-modifying therapy is sparse; HSCT evidence is limited and not definitively effective.

References (URLs and publication timing as available in retrieved evidence)

  • Ferdinandusse et al. Human Mutation (Sep 2007). https://doi.org/10.1002/humu.20535 (ferdinandusse2007clinicalbiochemicaland pages 1-2)
  • Carrozzo et al. Am J Med Genet A (Jul 2008). https://doi.org/10.1002/ajmg.a.32298 (carrozzo2008peroxisomalacyl‐coa‐oxidasedeficiency pages 1-2)
  • Rosewich et al. Neuropediatrics (Apr 2006). https://doi.org/10.1055/s-2006-923943 (rosewich12006pitfallinmetabolic pages 1-2)
  • Wang et al. J Inherit Metab Dis (Mar 2014). https://doi.org/10.1007/s10545-014-9698-3 (wang2014effectsofhematopoietic pages 1-2)
  • Hajj et al. Endocrinology (Apr 2012). https://doi.org/10.1210/en.2012-1137 (hajj2012theinflammatoryresponse pages 1-2)
  • Wanders et al. Adv Exp Med Biol (2021). https://doi.org/10.1007/978-3-030-60204-8_5 (wanders2021fattyacidoxidation pages 69-70)
  • Mohan et al. Mol Genet Metab (May 2023). https://doi.org/10.2139/ssrn.4330003 (mohan2023evaluatingthestrength pages 3-4)
  • Raas et al. Front Mol Neurosci (Apr 2023). https://doi.org/10.3389/fnmol.2023.1170313 (raas2023peroxisomaldefectsin pages 1-2)
  • Sarkar & Lipinski Cells (Oct 2024). https://doi.org/10.3390/cells13191655 (sarkar2024roleandfunction pages 9-10)
  • ClinicalTrials.gov NCT01668186. https://clinicaltrials.gov/study/NCT01668186
  • ClinicalTrials.gov NCT02171104. https://clinicaltrials.gov/study/NCT02171104

References

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