🔗

Mappings

MONDO

MONDO:0010247 X-linked cerebral adrenoleukodystrophy

👪

Inheritance

1

X-linked recessive inheritance HP:0001419

X-ALD follows X-linked recessive inheritance because pathogenic ABCD1 variants are transmitted on the X chromosome.

X-linked recessive inheritance

Show evidence (1 reference)

PMID:30544401 SUPPORT Human Clinical

"X-linked adrenoleukodystrophy (X-ALD) is a rare disorder caused by mutations in the ABCD1 gene, coding for peroxisomal membrane transporter adrenoleukodystrophy (ALD) protein."

This directly supports the inherited X-linked recessive pattern of X-ALD.

⚙

Pathophysiology

9

ABCD1-mediated peroxisomal transport defect

Pathogenic ABCD1 variants impair ALDP, an ATP-binding cassette transporter in the peroxisomal membrane that imports CoA-activated very long-chain fatty acids for degradation, initiating the biochemical disease cascade.

astrocyte link

ABCD1 link

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

ATPase-coupled transmembrane transporter activity link ↓ DECREASED

peroxisomal membrane link

Downstream

VLCFA accumulation in brain and spinal cord Peroxisomal transport failure drives toxic substrate accumulation in the nervous system and adrenal tissue.

Show evidence (3 references)

PMID:24316281 SUPPORT Other

"ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation."

This review directly defines ABCD1/ALDP as the peroxisomal VLCFA import step disrupted in X-ALD.

PMID:22889154 SUPPORT Other

"peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids"

Clinical management guidelines independently place ALDP in peroxisomal transmembrane VLCFA transport.

PMID:38077449 SUPPORT In Vitro

"X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder caused by pathogenic variants in the ABCD1 gene, leading to accumulation of saturated very long chain fatty acids (VLCFA) in body fluids and tissues including brain and spinal cord."

This directly supports the initiating ABCD1-driven peroxisomal transport defect and VLCFA accumulation.

VLCFA accumulation in brain and spinal cord

Accumulated saturated very long-chain fatty acids are a biochemical hallmark of X-ALD and contribute to tissue injury.

fatty acid beta-oxidation link ↓ DECREASED

Downstream

Oxidative stress VLCFA excess promotes redox imbalance and oxidative injury.

Adrenomyeloneuropathy axonopathy VLCFA accumulation is required for X-ALD phenotypes and contributes to the spinal-cord axonopathy branch through oxidative stress, energy shortage, and axon-glial interactions.

Adrenal gland VLCFA toxicity VLCFA accumulation also injures the adrenal cortex, predisposing to adrenal insufficiency.

Show evidence (3 references)

PMID:38077449 SUPPORT In Vitro

"AMN and cALD astrocytes exhibited lack of ABCD1 and accumulation of VLCFA, a biochemical hallmark of X-ALD disease."

This directly supports VLCFA accumulation as a core biochemical feature.

PMID:22014002 SUPPORT Human Clinical

"Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA)."

This supports the VLCFA metabolic defect in ALD.

PMID:22889154 SUPPORT Other

"A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."

This supports plasma and tissue VLCFA elevation as the biochemical consequence of ALDP dysfunction.

Oxidative stress

Oxidative stress contributes to cellular injury in X-ALD and amplifies the inflammatory cascade.

response to oxidative stress link ↑ INCREASED

Downstream

Astrocyte metabolic and inflammatory dysfunction Redox imbalance contributes to astrocytic metabolic failure and inflammatory activation.

Adrenomyeloneuropathy axonopathy Axonal oxidative stress and energy shortage are implicated in the dying-back axonopathy that underlies the AMN branch of X-ALD.

Show evidence (2 references)

PMID:35463999 SUPPORT Other

"research showed that VLCFA could induce oxidative stress and inflammation, leading to damage."

This directly supports oxidative stress as a pathogenic mechanism in X-ALD.

PMID:24316281 SUPPORT Other

"Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy."

This supports oxidative stress as part of the disease mechanism.

Astrocyte metabolic and inflammatory dysfunction

ABCD1-mutant astrocytes exhibit metabolic stress and pro-inflammatory signaling changes that help drive cerebral disease.

astrocyte link

inflammatory response link ↑ INCREASED

Downstream

Blood-brain barrier dysfunction Astrocyte dysfunction contributes to BBB injury and vascular leakage.

Show evidence (1 reference)

PMID:38077449 SUPPORT In Vitro

"Mitochondrial function analysis by Seahorse extracellular flux identified increased oxygen consumption and extracellular acidification rates in cALD astrocytes, yet the ATP levels were decreased. Molecular signaling identified increased phosphorylation of STAT3 in cALD astrocytes, and higher..."

This supports an astrocyte-centered inflammatory/metabolic dysfunction downstream of ABCD1 loss.

Blood-brain barrier dysfunction

Matrix metalloproteinase-mediated BBB injury is a distinct early step in cerebral ALD.

extracellular matrix organization link ↕ DYSREGULATED

Downstream

Microglial and macrophage activation Barrier injury promotes innate immune cell recruitment and activation.

Show evidence (2 references)

PMID:23185624 SUPPORT Human Clinical

"Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption."

This directly supports BBB dysfunction as a distinct pathogenic event.

PMID:23185624 SUPPORT Human Clinical

"MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier."

CSF MMP elevation supports matrix-metalloproteinase involvement in BBB breakdown.

Microglial and macrophage activation

Activated innate immune cells drive the inflammatory cerebral lesion in cALD.

microglial cell link macrophage link

microglial cell activation link ↑ INCREASED macrophage activation link ↑ INCREASED

Downstream

Inflammatory demyelination Innate immune activation propagates active white-matter destruction.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD."

This directly supports monocyte/macrophage activation in active cerebral ALD.

Inflammatory demyelination

Cerebral ALD is characterized by rapidly progressive inflammatory demyelination.

oligodendrocyte link

myelination link ↓ DECREASED

Downstream

Leukoencephalopathy The active cerebral inflammatory demyelinating lesion is represented clinically and radiographically as cerebral white-matter disease.

Cognitive impairment Progressive cerebral demyelination produces loss of cognition and executive function.

Behavioral abnormality White matter and frontal-subcortical injury contributes to behavioral and psychiatric change.

Visual loss Involvement of visual pathways contributes to progressive visual loss.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal."

This directly supports inflammatory demyelination as the cerebral lesion.

Adrenomyeloneuropathy axonopathy

ABCD1 mutations commonly manifest as adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting ascending and descending spinal cord tracts and sometimes peripheral nerves.

response to oxidative stress link ↑ INCREASED

Downstream

Progressive myelopathy Spinal-cord tract axonopathy manifests as slowly progressive myelopathy.

Spasticity The AMN spinal-cord axonopathy branch includes spasticity as a core manifestation.

Peripheral neuropathy In some patients the adrenomyeloneuropathy branch extends to peripheral nerve involvement.

Bladder and bowel dysfunction The AMN branch includes autonomic lower-tract involvement represented by bladder and bowel dysfunction.

Show evidence (1 reference)

PMID:24316281 SUPPORT Other

"The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy."

The review defines the AMN branch as a progressive spinal-cord axonopathy with possible peripheral neuropathy.

Adrenal gland VLCFA toxicity

Adrenal VLCFA accumulation contributes to adrenal cortex dysfunction and steroid deficiency.

Downstream

Adrenal insufficiency Adrenal cortex injury manifests clinically as primary adrenal insufficiency.

Show evidence (1 reference)

PMID:35291541 SUPPORT Human Clinical

"X-ALD can initially present as Addison's disease (primary adrenal insufficiency) as the accumulation of VLCFA most importantly occurs in the adrenal gland."

This supports adrenal involvement as a downstream consequence of VLCFA accumulation.

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Pathograph

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

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Phenotypes

9

Endocrine 1

Adrenal insufficiency Adrenal insufficiency (HP:0000846)

Show evidence (1 reference)

PMID:35291541 SUPPORT Human Clinical

"X-ALD can initially present as Addison's disease (primary adrenal insufficiency) as the accumulation of VLCFA most importantly occurs in the adrenal gland."

This directly supports adrenal insufficiency as a clinical phenotype.

Eye 1

Visual loss Visual loss (HP:0000572)

Show evidence (1 reference)

PMID:35291541 SUPPORT Human Clinical

"Our 20-year-old male patient, a known case of Addison's disease, presented with vision loss, neurologic symptoms, and psychiatric issues."

This directly supports vision loss as part of the X-ALD phenotype.

Musculoskeletal 1

Spasticity FREQUENT Spasticity (HP:0001257)

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

"AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction"

GeneReviews characterizes AMN by spasticity, supporting this as a frequent AMN-spectrum manifestation.

Nervous System 5

Leukoencephalopathy Leukoencephalopathy (HP:0002352)

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal."

This supports a cerebral demyelinating white-matter phenotype.

Behavioral abnormality Atypical behavior (HP:0000708)

Show evidence (1 reference)

PMID:35291541 SUPPORT Human Clinical

"psychiatric problems included primarily depressive disorder and mild psychotic behavior."

This supports behavioral and neurologic involvement in X-ALD.

Cognitive impairment Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:35291541 SUPPORT Human Clinical

"poor concentration and memory"

This supports cognitive impairment as part of the cerebral X-ALD phenotype.

Progressive myelopathy Myelopathy (HP:0002196)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:22889154 SUPPORT Other

"The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination."

This directly supports progressive myelopathy in the male X-ALD clinical spectrum.

Peripheral neuropathy Peripheral neuropathy (HP:0009830)

Show evidence (1 reference)

PMID:24316281 SUPPORT Other

"a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy."

This directly supports peripheral neuropathy as part of the AMN branch of X-ALD.

Other 1

Bladder and bowel dysfunction FREQUENT Abnormality of the bladder (HP:0000014)

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

"AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and bladder and bowel dysfunction"

GeneReviews characterizes AMN by bladder and bowel dysfunction, supporting this lower-tract phenotype in the X-ALD spectrum.

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Genetic Associations

1

ABCD1 (Causal loss-of-function variant)

Show evidence (2 references)

PMID:24316281 SUPPORT Other

"The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP)."

This directly supports ABCD1 as the causal gene for X-ALD.

CGGV:assertion_815e0f84-b530-4fd2-81a9-02e02bf352ee-2020-12-18T050000.000Z SUPPORT Other

ClinGen classifies the ABCD1-adrenoleukodystrophy relationship as definitive with X-linked inheritance.

💊

Treatments

3

Allogeneic hematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation MAXO:0000747

Early allogeneic HSCT can halt progression of active cerebral disease in appropriately selected patients.

Mechanism Target:

MODULATES Microglial and macrophage activation — Early HSCT is used to halt active cerebral disease, consistent with a disease-modifying effect on inflammatory innate immune-cell activation.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early."

Early HSCT can halt active cerebral progression, supporting a mechanism target within the inflammatory branch.

MODULATES Inflammatory demyelination — HSCT is disease-modifying only when the active cerebral demyelinating process is treated early.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early."

The treatment effect is on early active cerebral ALD progression.

Target Phenotypes: Leukoencephalopathy ↗ Cognitive impairment ↗

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early."

This directly supports HSCT as a disease-modifying treatment for cerebral ALD.

Hematopoietic stem cell gene therapy

Action: gene therapy MAXO:0001001

Gene-modified autologous hematopoietic stem cells are an emerging strategy for cerebral ALD when a matched donor is not available or to improve treatment options.

Mechanism Target:

RESTORES ABCD1-mediated peroxisomal transport defect — Lenti-D/eli-cel modifies autologous hematopoietic stem cells with a lentiviral vector encoding human adrenoleukodystrophy protein, aiming to restore ABCD1/ALDP expression in transplanted hematopoietic cells.

Show evidence (1 reference)

clinicaltrials:NCT03852498 SUPPORT Human Clinical

"A participant's blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein."

The trial describes ex vivo gene addition of human ALDP to autologous blood stem cells, supporting a restorative mechanism target at ABCD1/ALDP.

Target Phenotypes: Leukoencephalopathy ↗ Cognitive impairment ↗

Show evidence (1 reference)

PMID:35693884 SUPPORT Human Clinical

"hematopoietic stem cell gene therapy, where autologous hematopoietic stem cells are collected, manipulated ex vivo to overexpress the missing enzyme, and infused back into the patient."

This supports gene therapy as an emerging treatment paradigm for X-ALD.

Steroid replacement therapy

Action: Pharmacotherapy NCIT:C15986

Agent: therapeutic corticosteroid ↗

Steroid replacement pharmacotherapy is used to promptly treat confirmed primary adrenal insufficiency in X-ALD, with endocrinology-guided screening and management throughout childhood and later life.

Target Phenotypes: Adrenal insufficiency ↗

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

"confirmed adrenal insufficiency according to published steroid replacement guidelines"

GeneReviews explicitly recommends prompt steroid replacement for confirmed primary adrenocortical insufficiency in X-ALD.

🔬

Biochemical Markers

3

Very long-chain fatty acids (INCREASED)

Context: Plasma and tissue accumulation is a biochemical hallmark of X-ALD and a diagnostic readout of the ABCD1/ALDP transport defect.

Pathograph Readouts

Readout Of ABCD1-mediated peroxisomal transport defect Positive Diagnostic

Elevated plasma VLCFA reports impaired ALDP-mediated peroxisomal VLCFA transport.

Show evidence (1 reference)

PMID:22889154 SUPPORT Other

"A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."

The guideline review directly links the ALDP defect to elevated VLCFA.

Readout Of VLCFA accumulation in brain and spinal cord Positive Diagnostic

Elevated VLCFA measures the accumulating substrate pool represented by the VLCFA accumulation node.

Show evidence (1 reference)

PMID:38077449 SUPPORT In Vitro

"AMN and cALD astrocytes exhibited lack of ABCD1 and accumulation of VLCFA, a biochemical hallmark of X-ALD disease."

This identifies VLCFA accumulation as the biochemical hallmark that the biomarker measures.

Show evidence (2 references)

PMID:38077449 SUPPORT In Vitro

"X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder caused by pathogenic variants in the ABCD1 gene, leading to accumulation of saturated very long chain fatty acids (VLCFA) in body fluids and tissues including brain and spinal cord."

This directly supports VLCFA accumulation as a biochemical feature.

PMID:22889154 SUPPORT Other

"A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."

This supports VLCFA as a diagnostic plasma and tissue biomarker.

Chitotriosidase activity (INCREASED)

Context: CSF and plasma chitotriosidase track active cerebral ALD inflammation and predict post-transplant functional progression.

Pathograph Readouts

Readout Of Microglial and macrophage activation Positive Monitoring

Chitotriosidase activity reports the monocyte/macrophage activation branch in active cerebral ALD.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD."

The study selected chitotriosidase to measure active monocyte/macrophage biology in C-ALD.

Predicts Inflammatory demyelination Positive Prognostic

Higher pre-transplant plasma and CSF chitotriosidase predict subsequent functional progression in active C-ALD.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"activity levels of plasma and CSF chitotriosidase prior to transplant correlated with progression as determined by the Moser/Raymond functional score 1 year following transplantation"

The pre-transplant biomarker level predicted functional progression, supporting a prognostic readout link to the active demyelinating disease branch.

Show evidence (1 reference)

PMID:22014002 SUPPORT Human Clinical

"We document elevations in chitotriosidase activity in the plasma of patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs. controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n = 16, median 0..."

This directly supports chitotriosidase elevation as a biomarker of active cerebral disease.

CSF matrix metalloproteinase 10 (INCREASED)

Context: CSF MMP10 elevation is one of the matrix metalloproteinase signals that correlates with MRI Loes score and neurologic function in cerebral ALD.

Pathograph Readouts

Readout Of Blood-brain barrier dysfunction Positive Monitoring

CSF matrix metalloproteinase elevation reports BBB extracellular-matrix breakdown in active cerebral ALD.

Show evidence (1 reference)

PMID:23185624 SUPPORT Human Clinical

"MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier."

This links elevated CSF MMPs to BBB breakdown.

Correlates With Inflammatory demyelination Positive Prognostic

Higher CSF MMP concentrations correlate with radiographic inflammation and clinical neurologic severity.

Show evidence (1 reference)

PMID:23185624 SUPPORT Human Clinical

"MMP concentrations directly correlate to radiographic and clinical neurologic severity."

The biomarker correlates with radiographic and clinical severity of the active cerebral disease branch.

Show evidence (1 reference)

PMID:23185624 SUPPORT Human Clinical

"There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls."

This supports CSF MMP10 as an elevated biomarker in cerebral ALD.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from X-linked cerebral adrenoleukodystrophy:

Multiple sclerosis MONDO:0005301

Overlapping Features Inflammatory demyelinating disease that can overlap with cerebral ALD on a symptom basis, especially when white-matter lesions and neurologic deficits are present.

Distinguishing Features

X-ALD is suggested by elevated VLCFAs and ABCD1 pathogenic variants.
Prominent adrenal insufficiency strongly favors X-ALD over multiple sclerosis.

🔬

Clinical Trials

3

NCT03852498 PHASE_III COMPLETED

Phase 3 Lenti-D gene therapy study after myeloablative conditioning in boys with cerebral adrenoleukodystrophy.

Show evidence (1 reference)

clinicaltrials:NCT03852498 SUPPORT Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of Lenti-D Drug Product (also known as elivaldogene autotemcel or Skysona, hereafter referred to as eli-cel) after myeloablative conditioning with busulfan and fludarabine in participants with CALD."

This trial supports active clinical development of gene therapy for cerebral ALD.

NCT03231878 PHASE_II COMPLETED

Randomized MIN-102 (leriglitazone) study in men with adrenomyeloneuropathy due to X-linked adrenoleukodystrophy.

Show evidence (1 reference)

clinicaltrials:NCT03231878 SUPPORT Human Clinical

"This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter, two parallel-group study in male patients with the AMN phenotype of X-linked adrenoleukodystrophy (X-ALD) to assess the efficacy and safety of MIN-102 treatment."

This supports ongoing therapeutic development for the X-ALD spectrum.

NCT04528706 PHASE_II COMPLETED

Open-label MIN-102 (leriglitazone) study in boys with cerebral adrenoleukodystrophy before hematopoietic stem cell transplant.

Show evidence (1 reference)

clinicaltrials:NCT04528706 SUPPORT Human Clinical

"An Open-Label, multicenter study in male pediatric patients with cerebral x-linked adrenoleukodystrophy (cald) to assess the effects of MIN-102 treatment on disease progression prior to human stem cell transplant (HSCT)"

This supports clinical trial activity for treatment of cerebral ALD.

{ }

Source YAML

click to show

name: X-linked cerebral adrenoleukodystrophy
creation_date: "2026-04-15T00:00:00Z"
updated_date: "2026-05-20T22:03:56Z"
category: Mendelian
description: >-
  X-linked cerebral adrenoleukodystrophy is a peroxisomal ABCD1 disorder in
  which impaired ALDP-mediated transport of CoA-activated very long-chain fatty
  acids into peroxisomes reduces peroxisomal degradation and causes VLCFA
  accumulation in plasma, adrenal gland, brain, and spinal cord. The core
  metabolic defect branches into adrenal insufficiency, adrenomyeloneuropathy
  with progressive myelopathy and peripheral neuropathy, and the cerebral ALD
  pathway of oxidative stress, astrocyte inflammatory dysfunction,
  blood-brain-barrier injury, microglial/macrophage activation, inflammatory
  demyelination, and neurobehavioral or visual decline.
disease_term:
  preferred_term: X-linked cerebral adrenoleukodystrophy
  term:
    id: MONDO:0010247
    label: X-linked cerebral adrenoleukodystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010247
      label: X-linked cerebral adrenoleukodystrophy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
synonyms:
- X-ALD
- ALD
- CALD
- cALD
- childhood cerebral adrenoleukodystrophy
parents:
- hereditary disease
- leukodystrophy
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    X-ALD follows X-linked recessive inheritance because pathogenic ABCD1
    variants are transmitted on the X chromosome.
  evidence:
  - reference: PMID:30544401
    reference_title: "Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked adrenoleukodystrophy (X-ALD) is a rare disorder caused by
      mutations in the ABCD1 gene, coding for peroxisomal membrane transporter
      adrenoleukodystrophy (ALD) protein.
    explanation: >-
      This directly supports the inherited X-linked recessive pattern of X-ALD.
genetic:
- name: ABCD1
  association: Causal loss-of-function variant
  gene_term:
    preferred_term: ABCD1
    term:
      id: hgnc:61
      label: ABCD1
  notes: >-
    X-linked cerebral adrenoleukodystrophy is caused by pathogenic ABCD1
    variants that impair peroxisomal VLCFA transport and initiate the disease
    cascade.
  evidence:
  - reference: PMID:24316281
    reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The genetic bases for all different phenotypic variants of X-ALD are
      mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC)
      transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP).
    explanation: >-
      This directly supports ABCD1 as the causal gene for X-ALD.
  - reference: CGGV:assertion_815e0f84-b530-4fd2-81a9-02e02bf352ee-2020-12-18T050000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCD1 | HGNC:61 | adrenoleukodystrophy | MONDO:0018544 | XL | Definitive"
    explanation: >-
      ClinGen classifies the ABCD1-adrenoleukodystrophy relationship as
      definitive with X-linked inheritance.
pathophysiology:
- name: ABCD1-mediated peroxisomal transport defect
  description: >-
    Pathogenic ABCD1 variants impair ALDP, an ATP-binding cassette transporter
    in the peroxisomal membrane that imports CoA-activated very long-chain fatty
    acids for degradation, initiating the biochemical disease cascade.
  genes:
  - preferred_term: ABCD1
    term:
      id: hgnc:61
      label: ABCD1
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  molecular_functions:
  - preferred_term: ATPase-coupled transmembrane transporter activity
    term:
      id: GO:0042626
      label: ATPase-coupled transmembrane transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: very long-chain fatty acid metabolic process
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  chemical_entities:
  - preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
    modifier: INCREASED
  evidence:
  - reference: PMID:24316281
    reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol
      into the peroxisome for degradation.
    explanation: >-
      This review directly defines ABCD1/ALDP as the peroxisomal VLCFA import
      step disrupted in X-ALD.
  - reference: PMID:22889154
    reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      peroxisomal membrane protein ALDP which is involved in the transmembrane
      transport of very long-chain fatty acids
    explanation: >-
      Clinical management guidelines independently place ALDP in peroxisomal
      transmembrane VLCFA transport.
  - reference: PMID:38077449
    reference_title: "IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder
      caused by pathogenic variants in the ABCD1 gene, leading to accumulation
      of saturated very long chain fatty acids (VLCFA) in body fluids and
      tissues including brain and spinal cord.
    explanation: >-
      This directly supports the initiating ABCD1-driven peroxisomal transport
      defect and VLCFA accumulation.
  downstream:
  - target: VLCFA accumulation in brain and spinal cord
    description: >-
      Peroxisomal transport failure drives toxic substrate accumulation in the
      nervous system and adrenal tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22889154
      reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."
      explanation: >-
        The guideline review directly links ALDP defect to elevated VLCFA in
        plasma and tissues.
- name: VLCFA accumulation in brain and spinal cord
  description: >-
    Accumulated saturated very long-chain fatty acids are a biochemical hallmark
    of X-ALD and contribute to tissue injury.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: 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:38077449
    reference_title: "IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AMN and cALD astrocytes exhibited lack of ABCD1 and accumulation of VLCFA,
      a biochemical hallmark of X-ALD disease.
    explanation: >-
      This directly supports VLCFA accumulation as a core biochemical feature.
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder
      characterized by the abnormal beta-oxidation of very long chain fatty
      acids (VLCFA).
    explanation: >-
      This supports the VLCFA metabolic defect in ALD.
  - reference: PMID:22889154
    reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."
    explanation: >-
      This supports plasma and tissue VLCFA elevation as the biochemical
      consequence of ALDP dysfunction.
  downstream:
  - target: Oxidative stress
    description: >-
      VLCFA excess promotes redox imbalance and oxidative injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35463999
      reference_title: "The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        research showed that VLCFA could induce oxidative stress and inflammation,
        leading to damage.
      explanation: >-
        The review supports VLCFA-induced oxidative and inflammatory injury.
  - target: Adrenomyeloneuropathy axonopathy
    description: >-
      VLCFA accumulation is required for X-ALD phenotypes and contributes to the
      spinal-cord axonopathy branch through oxidative stress, energy shortage,
      and axon-glial interactions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Oxidative stress and energy shortage in axons.
    - Axon-glial interactions.
    evidence:
    - reference: PMID:24316281
      reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Although the accumulation of very long-chain fatty acids appears to be
        essential for the pathomechanism of all phenotypes
      explanation: >-
        The review supports VLCFA accumulation as an essential upstream feature
        across X-ALD phenotypes, including the axonopathy branch.
  - target: Adrenal gland VLCFA toxicity
    description: >-
      VLCFA accumulation also injures the adrenal cortex, predisposing to
      adrenal insufficiency.
    causal_link_type: DIRECT
- name: Oxidative stress
  description: >-
    Oxidative stress contributes to cellular injury in X-ALD and amplifies the
    inflammatory cascade.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:35463999
    reference_title: "The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      research showed that VLCFA could induce oxidative stress and inflammation,
      leading to damage.
    explanation: >-
      This directly supports oxidative stress as a pathogenic mechanism in X-ALD.
  - reference: PMID:24316281
    reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cell autonomous processes such as oxidative stress and energy shortage in
      axons as well as non-cell autonomous processes involving axon-glial
      interactions seem pertinent to the dying-back axonopathy.
    explanation: >-
      This supports oxidative stress as part of the disease mechanism.
  downstream:
  - target: Astrocyte metabolic and inflammatory dysfunction
    description: >-
      Redox imbalance contributes to astrocytic metabolic failure and
      inflammatory activation.
    causal_link_type: DIRECT
  - target: Adrenomyeloneuropathy axonopathy
    description: >-
      Axonal oxidative stress and energy shortage are implicated in the
      dying-back axonopathy that underlies the AMN branch of X-ALD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Energy shortage in axons.
    - Axon-glial interactions.
    evidence:
    - reference: PMID:24316281
      reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Cell autonomous processes such as oxidative stress and energy shortage in
        axons as well as non-cell autonomous processes involving axon-glial
        interactions seem pertinent to the dying-back axonopathy.
      explanation: >-
        This explicitly links oxidative stress, axonal energy shortage, and
        axon-glial interactions to the AMN axonopathy branch.
- name: Astrocyte metabolic and inflammatory dysfunction
  description: >-
    ABCD1-mutant astrocytes exhibit metabolic stress and pro-inflammatory
    signaling changes that help drive cerebral disease.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:38077449
    reference_title: "IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mitochondrial function analysis by Seahorse extracellular flux identified
      increased oxygen consumption and extracellular acidification rates in cALD
      astrocytes, yet the ATP levels were decreased. Molecular signaling
      identified increased phosphorylation of STAT3 in cALD astrocytes, and
      higher proinflammatory cytokine and Toll like receptor (TLR) expression.
    explanation: >-
      This supports an astrocyte-centered inflammatory/metabolic dysfunction
      downstream of ABCD1 loss.
  downstream:
  - target: Blood-brain barrier dysfunction
    description: >-
      Astrocyte dysfunction contributes to BBB injury and vascular leakage.
    causal_link_type: DIRECT
- name: Blood-brain barrier dysfunction
  description: >-
    Matrix metalloproteinase-mediated BBB injury is a distinct early step in
    cerebral ALD.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23185624
    reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuroimaging in cALD shows inflammatory changes and indicates
      blood-brain-barrier (BBB) disruption.
    explanation: >-
      This directly supports BBB dysfunction as a distinct pathogenic event.
  - reference: PMID:23185624
    reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MMPs were found to be elevated in the CSF of boys with cALD and may
      mechanistically contribute to the breakdown of the blood-brain-barrier.
    explanation: >-
      CSF MMP elevation supports matrix-metalloproteinase involvement in BBB
      breakdown.
  downstream:
  - target: Microglial and macrophage activation
    description: >-
      Barrier injury promotes innate immune cell recruitment and activation.
    causal_link_type: DIRECT
- name: Microglial and macrophage activation
  description: >-
    Activated innate immune cells drive the inflammatory cerebral lesion in
    cALD.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: microglial cell activation
    term:
      id: GO:0001774
      label: microglial cell activation
    modifier: INCREASED
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: INCREASED
  evidence:
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As cellular infiltration has been observed in C-ALD, including activation
      of monocytes and macrophages, we evaluated the activity of chitotriosidase
      in the plasma and spinal fluid of boys with active C-ALD.
    explanation: >-
      This directly supports monocyte/macrophage activation in active cerebral
      ALD.
  downstream:
  - target: Inflammatory demyelination
    description: >-
      Innate immune activation propagates active white-matter destruction.
    causal_link_type: DIRECT
- name: Inflammatory demyelination
  description: >-
    Cerebral ALD is characterized by rapidly progressive inflammatory
    demyelination.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 35-40% of children with ALD, an acute inflammatory process occurs in
      the central nervous system (CNS) leading to demyelination that is rapidly
      progressive, debilitating and ultimately fatal.
    explanation: >-
      This directly supports inflammatory demyelination as the cerebral lesion.
  downstream:
  - target: Leukoencephalopathy
    description: >-
      The active cerebral inflammatory demyelinating lesion is represented
      clinically and radiographically as cerebral white-matter disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22889154
      reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical spectrum in males with X-ALD ranges from isolated
        adrenocortical insufficiency and slowly progressive myelopathy to
        devastating cerebral demyelination.
      explanation: >-
        The guideline review directly identifies cerebral demyelination in the
        X-ALD clinical spectrum.
  - target: Cognitive impairment
    description: >-
      Progressive cerebral demyelination produces loss of cognition and executive
      function.
    causal_link_type: DIRECT
  - target: Behavioral abnormality
    description: >-
      White matter and frontal-subcortical injury contributes to behavioral and
      psychiatric change.
    causal_link_type: DIRECT
  - target: Visual loss
    description: >-
      Involvement of visual pathways contributes to progressive visual loss.
    causal_link_type: DIRECT
- name: Adrenomyeloneuropathy axonopathy
  description: >-
    ABCD1 mutations commonly manifest as adrenomyeloneuropathy, a slowly
    progressive dying-back axonopathy affecting ascending and descending spinal
    cord tracts and sometimes peripheral nerves.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:24316281
    reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy,
      a slowly progressive dying-back axonopathy affecting both ascending and
      descending spinal cord tracts as well as in some cases, a peripheral
      neuropathy.
    explanation: >-
      The review defines the AMN branch as a progressive spinal-cord axonopathy
      with possible peripheral neuropathy.
  downstream:
  - target: Progressive myelopathy
    description: >-
      Spinal-cord tract axonopathy manifests as slowly progressive myelopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22889154
      reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical spectrum in males with X-ALD ranges from isolated
        adrenocortical insufficiency and slowly progressive myelopathy to
        devastating cerebral demyelination.
      explanation: >-
        The guideline review lists slowly progressive myelopathy as part of the
        male X-ALD spectrum.
  - target: Spasticity
    description: >-
      The AMN spinal-cord axonopathy branch includes spasticity as a core
      manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301491
      reference_title: "X-Linked Adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and
        bladder and bowel dysfunction
      explanation: >-
        GeneReviews lists spasticity among defining AMN manifestations.
  - target: Peripheral neuropathy
    description: >-
      In some patients the adrenomyeloneuropathy branch extends to peripheral
      nerve involvement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24316281
      reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        a slowly progressive dying-back axonopathy affecting both ascending and
        descending spinal cord tracts as well as in some cases, a peripheral
        neuropathy.
      explanation: >-
        The review directly states that peripheral neuropathy can occur in the
        AMN branch.
  - target: Bladder and bowel dysfunction
    description: >-
      The AMN branch includes autonomic lower-tract involvement represented by
      bladder and bowel dysfunction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301491
      reference_title: "X-Linked Adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and
        bladder and bowel dysfunction
      explanation: >-
        GeneReviews lists bladder and bowel dysfunction among AMN manifestations.
- name: Adrenal gland VLCFA toxicity
  description: >-
    Adrenal VLCFA accumulation contributes to adrenal cortex dysfunction and
    steroid deficiency.
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ALD can initially present as Addison's disease (primary adrenal
      insufficiency) as the accumulation of VLCFA most importantly occurs in
      the adrenal gland.
    explanation: >-
      This supports adrenal involvement as a downstream consequence of VLCFA
      accumulation.
  downstream:
  - target: Adrenal insufficiency
    description: >-
      Adrenal cortex injury manifests clinically as primary adrenal
      insufficiency.
    causal_link_type: DIRECT
phenotypes:
- name: Adrenal insufficiency
  category: Endocrine
  description: >-
    Primary adrenal failure is a common initial or isolated manifestation of
    X-ALD.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ALD can initially present as Addison's disease (primary adrenal
      insufficiency) as the accumulation of VLCFA most importantly occurs in
      the adrenal gland.
    explanation: >-
      This directly supports adrenal insufficiency as a clinical phenotype.
- name: Leukoencephalopathy
  category: Neurologic
  description: >-
    Cerebral X-ALD causes inflammatory demyelinating white-matter disease.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 35-40% of children with ALD, an acute inflammatory process occurs in
      the central nervous system (CNS) leading to demyelination that is rapidly
      progressive, debilitating and ultimately fatal.
    explanation: >-
      This supports a cerebral demyelinating white-matter phenotype.
- name: Behavioral abnormality
  category: Neurologic
  description: >-
    Cerebral disease may be accompanied by psychiatric and behavioral
    disturbance.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      psychiatric problems included primarily depressive disorder and mild
      psychotic behavior.
    explanation: >-
      This supports behavioral and neurologic involvement in X-ALD.
- name: Cognitive impairment
  category: Neurologic
  description: >-
    Cerebral inflammatory disease causes progressive cognitive decline and
    neurologic dysfunction.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      poor concentration and memory
    explanation: >-
      This supports cognitive impairment as part of the cerebral X-ALD
      phenotype.
- name: Visual loss
  category: Ophthalmologic
  description: >-
    Visual pathway involvement can contribute to progressive vision loss.
  phenotype_term:
    preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our 20-year-old male patient, a known case of Addison's disease,
      presented with vision loss, neurologic symptoms, and psychiatric issues.
    explanation: >-
      This directly supports vision loss as part of the X-ALD phenotype.
- name: Progressive myelopathy
  category: Neurologic
  description: >-
    Males with X-ALD can develop slowly progressive myelopathy as part of the
    adrenomyeloneuropathy branch.
  phenotype_term:
    preferred_term: slowly progressive myelopathy
    term:
      id: HP:0002196
      label: Myelopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22889154
    reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical spectrum in males with X-ALD ranges from isolated
      adrenocortical insufficiency and slowly progressive myelopathy to
      devastating cerebral demyelination.
    explanation: >-
      This directly supports progressive myelopathy in the male X-ALD clinical
      spectrum.
- name: Spasticity
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Spasticity is a core AMN manifestation within the X-ALD spectrum.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20301491
    reference_title: "X-Linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and
      bladder and bowel dysfunction
    explanation: >-
      GeneReviews characterizes AMN by spasticity, supporting this as a frequent
      AMN-spectrum manifestation.
- name: Peripheral neuropathy
  category: Neurologic
  description: >-
    Peripheral neuropathy can accompany the adrenomyeloneuropathy axonopathy
    branch.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:24316281
    reference_title: "Pathophysiology of X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a slowly progressive dying-back axonopathy affecting both ascending and
      descending spinal cord tracts as well as in some cases, a peripheral
      neuropathy.
    explanation: >-
      This directly supports peripheral neuropathy as part of the AMN branch of
      X-ALD.
- name: Bladder and bowel dysfunction
  category: Genitourinary
  frequency: FREQUENT
  description: >-
    Bladder and bowel dysfunction are AMN manifestations in the X-ALD spectrum;
    the ontology mapping uses the closest bladder abnormality term for the
    lower-tract component of this combined clinical feature.
  phenotype_term:
    preferred_term: bladder dysfunction
    term:
      id: HP:0000014
      label: Abnormality of the bladder
  evidence:
  - reference: PMID:20301491
    reference_title: "X-Linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AMN is characterized by leg weakness, spasticity, clumsy gait, pain, and
      bladder and bowel dysfunction
    explanation: >-
      GeneReviews characterizes AMN by bladder and bowel dysfunction, supporting
      this lower-tract phenotype in the X-ALD spectrum.
biochemical:
- name: Very long-chain fatty acids
  biomarker_term:
    preferred_term: Very long-chain fatty acid
    term:
      id: NCIT:C68439
      label: Very Long Chain Fatty Acid
  presence: INCREASED
  context: >-
    Plasma and tissue accumulation is a biochemical hallmark of X-ALD and a
    diagnostic readout of the ABCD1/ALDP transport defect.
  readouts:
  - target: ABCD1-mediated peroxisomal transport defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated plasma VLCFA reports impaired ALDP-mediated peroxisomal VLCFA
      transport.
    evidence:
    - reference: PMID:22889154
      reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."
      explanation: >-
        The guideline review directly links the ALDP defect to elevated VLCFA.
  - target: VLCFA accumulation in brain and spinal cord
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated VLCFA measures the accumulating substrate pool represented by the
      VLCFA accumulation node.
    evidence:
    - reference: PMID:38077449
      reference_title: "IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        AMN and cALD astrocytes exhibited lack of ABCD1 and accumulation of VLCFA,
        a biochemical hallmark of X-ALD disease.
      explanation: >-
        This identifies VLCFA accumulation as the biochemical hallmark that the
        biomarker measures.
  evidence:
  - reference: PMID:38077449
    reference_title: "IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder
      caused by pathogenic variants in the ABCD1 gene, leading to accumulation
      of saturated very long chain fatty acids (VLCFA) in body fluids and
      tissues including brain and spinal cord.
    explanation: >-
      This directly supports VLCFA accumulation as a biochemical feature.
  - reference: PMID:22889154
    reference_title: "X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A defect in ALDP results in elevated levels of VLCFA in plasma and tissues."
    explanation: >-
      This supports VLCFA as a diagnostic plasma and tissue biomarker.
- name: Chitotriosidase activity
  biomarker_term:
    preferred_term: Chitotriosidase-1 measurement
    term:
      id: NCIT:C187795
      label: Chitotriosidase-1 Measurement
  presence: INCREASED
  context: >-
    CSF and plasma chitotriosidase track active cerebral ALD inflammation and
    predict post-transplant functional progression.
  readouts:
  - target: Microglial and macrophage activation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Chitotriosidase activity reports the monocyte/macrophage activation branch
      in active cerebral ALD.
    evidence:
    - reference: PMID:22014002
      reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        As cellular infiltration has been observed in C-ALD, including activation
        of monocytes and macrophages, we evaluated the activity of chitotriosidase
        in the plasma and spinal fluid of boys with active C-ALD.
      explanation: >-
        The study selected chitotriosidase to measure active monocyte/macrophage
        biology in C-ALD.
  - target: Inflammatory demyelination
    relationship: PREDICTS
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher pre-transplant plasma and CSF chitotriosidase predict subsequent
      functional progression in active C-ALD.
    evidence:
    - reference: PMID:22014002
      reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        activity levels of plasma and CSF chitotriosidase prior to transplant
        correlated with progression as determined by the Moser/Raymond functional
        score 1 year following transplantation
      explanation: >-
        The pre-transplant biomarker level predicted functional progression,
        supporting a prognostic readout link to the active demyelinating disease
        branch.
  evidence:
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We document elevations in chitotriosidase activity in the plasma of
      patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs.
      controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of
      C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n =
      16, median 0 ng/mL/hr, p < 0.0001).
    explanation: >-
      This directly supports chitotriosidase elevation as a biomarker of active
      cerebral disease.
- name: CSF matrix metalloproteinase 10
  biomarker_term:
    preferred_term: Matrix metalloproteinase 10 measurement
    term:
      id: NCIT:C209604
      label: Matrix Metalloproteinase 10 Measurement
  presence: INCREASED
  context: >-
    CSF MMP10 elevation is one of the matrix metalloproteinase signals that
    correlates with MRI Loes score and neurologic function in cerebral ALD.
  readouts:
  - target: Blood-brain barrier dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      CSF matrix metalloproteinase elevation reports BBB extracellular-matrix
      breakdown in active cerebral ALD.
    evidence:
    - reference: PMID:23185624
      reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MMPs were found to be elevated in the CSF of boys with cALD and may
        mechanistically contribute to the breakdown of the blood-brain-barrier.
      explanation: >-
        This links elevated CSF MMPs to BBB breakdown.
  - target: Inflammatory demyelination
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher CSF MMP concentrations correlate with radiographic inflammation and
      clinical neurologic severity.
    evidence:
    - reference: PMID:23185624
      reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MMP concentrations directly correlate to radiographic and clinical
        neurologic severity.
      explanation: >-
        The biomarker correlates with radiographic and clinical severity of the
        active cerebral disease branch.
  evidence:
  - reference: PMID:23185624
    reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total
      protein in the CSF of boys with cALD compared to controls.
    explanation: >-
      This supports CSF MMP10 as an elevated biomarker in cerebral ALD.
diagnosis:
- name: Brain magnetic resonance imaging
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  description: >-
    MRI identifies inflammatory white-matter lesions and helps stage cerebral
    disease using the Loes score.
  results: >-
    Demonstrates active cerebral involvement and disease burden.
  evidence:
  - reference: PMID:23185624
    reference_title: "Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used a multiplex assay to correlate the concentration of MMPs in
      cerebrospinal fluid and plasma to the severity of brain inflammation as
      determined by the ALD MRI (Loes) score and the neurologic function score.
    explanation: >-
      This directly supports MRI and Loes scoring as a way to assess cerebral
      disease severity.
- name: Plasma VLCFA analysis
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >-
    Measurement of plasma VLCFAs provides the hallmark biochemical diagnostic
    signal for X-ALD.
  results: >-
    Identifies the biochemical signature of ABCD1 deficiency.
  evidence:
  - reference: PMID:30544401
    reference_title: "Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ALD, confirmed based on elevated VLCFA concentrations and genetic testing
      of ABCD1 gene.
    explanation: >-
      This directly supports plasma VLCFA measurement as part of diagnosis.
- name: ABCD1 sequencing
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >-
    Molecular testing confirms the causative ABCD1 variant and supports family
    counseling.
  results: >-
    Confirms the molecular diagnosis and inheritance pattern.
  evidence:
  - reference: PMID:30544401
    reference_title: "Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ALD, confirmed based on elevated VLCFA concentrations and genetic testing
      of ABCD1 gene.
    explanation: >-
      This directly supports ABCD1 sequencing as a confirmatory diagnostic test.
- name: Adrenal function testing
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >-
    Cortisol and ACTH testing can identify adrenal insufficiency that may be an
    initial clue to X-ALD.
  results: >-
    Detects Addison disease / primary adrenal insufficiency.
  evidence:
  - reference: PMID:35291541
    reference_title: "X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-ALD can initially present as Addison's disease (primary adrenal
      insufficiency) as the accumulation of VLCFA most importantly occurs in the
      adrenal gland.
    explanation: >-
      This supports adrenal testing when adrenal insufficiency is the presenting
      feature.
differential_diagnoses:
- name: Multiple sclerosis
  description: >-
    Inflammatory demyelinating disease that can overlap with cerebral ALD on a
    symptom basis, especially when white-matter lesions and neurologic deficits
    are present.
  disease_term:
    preferred_term: multiple sclerosis
    term:
      id: MONDO:0005301
      label: multiple sclerosis
  distinguishing_features:
  - X-ALD is suggested by elevated VLCFAs and ABCD1 pathogenic variants.
  - Prominent adrenal insufficiency strongly favors X-ALD over multiple sclerosis.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation
  description: >-
    Early allogeneic HSCT can halt progression of active cerebral disease in
    appropriately selected patients.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: Microglial and macrophage activation
    treatment_effect: MODULATES
    description: >-
      Early HSCT is used to halt active cerebral disease, consistent with a
      disease-modifying effect on inflammatory innate immune-cell activation.
    evidence:
    - reference: PMID:22014002
      reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease
        progression in cerebral ALD (C-ALD) if performed early.
      explanation: >-
        Early HSCT can halt active cerebral progression, supporting a mechanism
        target within the inflammatory branch.
  - target: Inflammatory demyelination
    treatment_effect: MODULATES
    description: >-
      HSCT is disease-modifying only when the active cerebral demyelinating
      process is treated early.
    evidence:
    - reference: PMID:22014002
      reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease
        progression in cerebral ALD (C-ALD) if performed early.
      explanation: >-
        The treatment effect is on early active cerebral ALD progression.
  target_phenotypes:
  - preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:22014002
    reference_title: "Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease
      progression in cerebral ALD (C-ALD) if performed early.
    explanation: >-
      This directly supports HSCT as a disease-modifying treatment for cerebral
      ALD.
- name: Hematopoietic stem cell gene therapy
  description: >-
    Gene-modified autologous hematopoietic stem cells are an emerging strategy
    for cerebral ALD when a matched donor is not available or to improve
    treatment options.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: ABCD1-mediated peroxisomal transport defect
    treatment_effect: RESTORES
    description: >-
      Lenti-D/eli-cel modifies autologous hematopoietic stem cells with a
      lentiviral vector encoding human adrenoleukodystrophy protein, aiming to
      restore ABCD1/ALDP expression in transplanted hematopoietic cells.
    evidence:
    - reference: clinicaltrials:NCT03852498
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A participant's blood stem cells will be collected and modified
        (transduced) using the Lenti-D lentiviral vector encoding human
        adrenoleukodystrophy protein.
      explanation: >-
        The trial describes ex vivo gene addition of human ALDP to autologous
        blood stem cells, supporting a restorative mechanism target at ABCD1/ALDP.
  target_phenotypes:
  - preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:35693884
    reference_title: "Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hematopoietic stem cell gene therapy, where autologous hematopoietic stem
      cells are collected, manipulated ex vivo to overexpress the missing enzyme,
      and infused back into the patient.
    explanation: >-
      This supports gene therapy as an emerging treatment paradigm for X-ALD.
- name: Steroid replacement therapy
  description: >-
    Steroid replacement pharmacotherapy is used to promptly treat confirmed
    primary adrenal insufficiency in X-ALD, with endocrinology-guided screening
    and management throughout childhood and later life.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: therapeutic corticosteroid
      term:
        id: NCIT:C211
        label: Therapeutic Corticosteroid
  target_phenotypes:
  - preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:20301491
    reference_title: "X-Linked Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      confirmed adrenal insufficiency according to published steroid replacement
      guidelines
    explanation: >-
      GeneReviews explicitly recommends prompt steroid replacement for confirmed
      primary adrenocortical insufficiency in X-ALD.
clinical_trials:
- name: NCT03852498
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase 3 Lenti-D gene therapy study after myeloablative conditioning in
    boys with cerebral adrenoleukodystrophy.
  evidence:
  - reference: clinicaltrials:NCT03852498
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      Lenti-D Drug Product (also known as elivaldogene autotemcel or Skysona,
      hereafter referred to as eli-cel) after myeloablative conditioning with
      busulfan and fludarabine in participants with CALD.
    explanation: >-
      This trial supports active clinical development of gene therapy for
      cerebral ALD.
- name: NCT03231878
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Randomized MIN-102 (leriglitazone) study in men with adrenomyeloneuropathy
    due to X-linked adrenoleukodystrophy.
  evidence:
  - reference: clinicaltrials:NCT03231878
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a Phase II/III, randomized, double-blind, placebo-controlled,
      multicenter, two parallel-group study in male patients with the AMN
      phenotype of X-linked adrenoleukodystrophy (X-ALD) to assess the efficacy
      and safety of MIN-102 treatment.
    explanation: >-
      This supports ongoing therapeutic development for the X-ALD spectrum.
- name: NCT04528706
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Open-label MIN-102 (leriglitazone) study in boys with cerebral
    adrenoleukodystrophy before hematopoietic stem cell transplant.
  evidence:
  - reference: clinicaltrials:NCT04528706
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An Open-Label, multicenter study in male pediatric patients with cerebral
      x-linked adrenoleukodystrophy (cald) to assess the effects of MIN-102
      treatment on disease progression prior to human stem cell transplant
      (HSCT)
    explanation: >-
      This supports clinical trial activity for treatment of cerebral ALD.
references:
- reference: PMID:20301491
  title: X-Linked Adrenoleukodystrophy.
  tags:
  - GeneReviews
datasets: []

📚

References & Deep Research

References

1

PMID:20301491

X-Linked Adrenoleukodystrophy.

No top-level findings curated for this source.

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of X-linked cerebral adrenoleukodystrophy. Core disease mechanisms, molecular...

Asta Scientific Corpus Retrieval 18 citations 2026-04-15T19:37:45.469151

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of X-linked cerebral adrenoleukodystrophy. Core disease mechanisms, molecular...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 18
Snippets retrieved: 20

Relevant Papers

[1] The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

Authors: Jiayu Yu, Ting Chen, Xin Guo, M. I. Zafar, Hui-qing Li et al.
Year: 2022
Venue: Frontiers in Nutrition
URL: https://www.semanticscholar.org/paper/32394667c48e7799777e1785035b36a84a344773
DOI: 10.3389/fnut.2022.864358
PMID: 35463999
PMCID: 9024313
Citations: 14
Summary: The evidence that oxidative stress and inflammation are increased in patients with X-ALD also proves that it is a potential mechanism of brain and adrenal damage, and normalizing the redox balance becomes a critical therapeutic target.
Evidence snippets:
Snippet 1 (score: 0.625) > X-linked adrenoleukodystrophy (X-ALD) is an inherited disease caused by a mutation in the ABCD1 gene encoding a peroxisomal transmembrane protein. It is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) in body fluids and tissues, leading to progressive demyelination and adrenal insufficiency. ALD has various phenotypes, among which the most common and severe is childhood cerebral adrenoleukodystrophy (CCALD). The pathophysiological mechanisms of ALD remain unclear, but some in vitro/in vivo research showed that VLCFA could induce oxidative stress and inflammation, leading to damage. In addition, the evidence that oxidative stress and inflammation are increased in patients with X-ALD also proves that it is a potential mechanism of brain and adrenal damage. Therefore, normalizing the redox balance becomes a critical therapeutic target. This study focuses on the possible predictors of the severity and progression of X-ALD, the potential mechanisms of pathogenesis, and the promising targeted drugs involved in oxidative stress and inflammation.

[2] X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan

Authors: M. Ghori, Rameen A Molani, Prof Mohsina N Ibrahim, M. Hanif, Jamal Jamal Raza
Year: 2022
Venue: Cureus
URL: https://www.semanticscholar.org/paper/e0cc39d209991516a5c369376ff21ab8e91ed582
DOI: 10.7759/cureus.21837
PMID: 35291541
PMCID: 8896247
Citations: 3
Summary: The purpose of this case report is to spread knowledge and understanding of X-ALD, so that it can be ruled out as the potential cause of adrenal insufficiency in young patients, particularly males diagnosed with Addison's disease.
Evidence snippets:
Snippet 1 (score: 0.617) > Adrenoleukodystrophy (ALD) is an X-linked progressive neurodegenerative disorder. It is characterized by the accumulation of very long chain fatty acid (VLCFA) due to the mutation of ABCD1 gene-encoded protein adrenoleukodystrophy protein (ALDP) [1]. > It has an incidence of 1:17,000 in males, majorly involving a mutation of the ABCD1 gene, making it the most common inherited peroxisomal disorder. Clinically, the phenotypes of X-linked adrenoleukodystrophy (X-ALD) in males range from Addison-only to cerebral ALD (CALD) involving three different stages: childhood, adolescence, and adult to adrenomyeloneuropathy (AMN). Addison-only X-ALD is characterized by adrenal insufficiency. In contrast, cerebral ALD is rapidly progressive myelopathy. Moreover, patients with X-ALD are slowly progressive and eventually develop AMN in adulthood at the third or fourth decade of life [2]. > Clinical progression of this disease involves intellectual deficits, communication disorders, and eventually paralysis, coma, and death [1]. > While the most common form of X-ALD involves the ABCD1 gene, the etiology of this disease is still unclear. Due to this, there are no effective treatment modalities and known cures in the late stages. However, early diagnosis and stem cell therapy may show significant results [3].

[3] Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy

Authors: T. Płatek, E. Orso, B. Zapała, A. Polus, B. Kieć-Wilk et al.
Year: 2018
Venue: Medicine
URL: https://www.semanticscholar.org/paper/1a7f134311311152aabb5257c31c4af224fcf320
DOI: 10.1097/MD.0000000000013353
PMID: 30544401
PMCID: 6310492
Citations: 5
Summary: It is suggested that decreased synthesis of BAs may be an additional dysfunction as a consequence of the ABCD1 c.659T>C, p.(Leu220Pro) mutation and may be further evidence that disturbed cholesterol metabolism is important in the pathology of ALD.
Evidence snippets:
Snippet 1 (score: 0.560) > X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a rare genetic neurodegenerative disease with recessive inheritance, linked to the X chromosome. X-ALD is characterized by the accumulation of saturated, unbranched very long chain fatty acids (VLCFAs) with more than 22 carbon atoms (VLCFA) in blood and tissues. A known cause of the disease is mutations in the ABCD1 gene encoding the ALD-protein (ALDP) transporting VLCFA into peroxisomes for degradation by the enzymes of the beta-oxidation pathway. Two main phenotypes are known: adult adrenomyeloneuropathy (AMN) and the cerebral inflammatory form of adrenoleukodystrophy (CALD). [1] AMN occurs in men and with disease manifestation appearing between the ages of 20 and 40. AMN is characterized by a noninflammatory, slowly progressive neuropathy within the spinal cord and peripheral nerves. [2] The main symptoms include spastic paraparesis, sensory disturbances, and overactive bladder. Some patients with AMN have adrenal insufficiency. [2] The second phenotype CALD with inflammatory involvement is very severe, together with rapidly progressive decline in cognitive function and neurological disorders. The immune response in CALD and AMN varies and induction of the pathology may depend on different lipid classes. The incidence of X-ALD is estimated to be about 1:17 000 live births, which is considered the most common peroxisomal disease and inherited disease of the white matter of the central nervous system. [3] Within 1 family different forms of the disease with various levels of severity can occur, without any link between genotype and X-ALD phenotype, which suggests involvement of other mechanisms including environmental factors. Moreover, monozygotic twins were reported to demonstrate differing phenotypes. [4] Many studies have been done to search for phenotype modifying genes in ALD. Genes associated with fatty acid metabolism (ABCD2, ABCD3, and ABCD4), inflammation (TNFalpha, MOG, CD1, IL6, HLA, and SOD2), and vitamin B 12
Snippet 2 (score: 0.545) > Rationale: X-linked adrenoleukodystrophy (X-ALD) is a rare disorder caused by mutations in the ABCD1 gene, coding for peroxisomal membrane transporter adrenoleukodystrophy (ALD) protein. The disease is characterized by accumulation of very long chain fatty acids (VLCFAs) in tissues. Adult adrenomyeloneuropathy (AMN) and the cerebral inflammatory form of ALD are the main phenotypes presenting various symptoms. Patient concerns: We report a case of 37-year-old patient with diagnosis of X-ALD, confirmed based on elevated VLCFA concentrations and genetic testing of ABCD1 gene. The complete clinical picture in the patient indicates AMN phenotype with cerebral involvement. Diagnoses: The reduced synthesis of unconjugated cholic and chenodeoxycholic acids, and the reduction to 28% to 29% of peroxisomal beta-oxidation of behenic acid and normal peroxisomal metabolism of pristanic and palmitic acid were observed in the X-ALD patient. Sanger sequencing of major genes involved in primary bile acid (BA) synthesis failed to identify pathogenic mutations of the investigated set of genes. Interventions: Plasma concentrations of BAs, VLCFAs, and beta-oxidation of C22:0, C16:0, and pristanic acid were studied in primary skin fibroblasts of the patient. In addition, we performed sequencing of the ABCD1, ABCD3, CYP7A1, CYP7B1, CYP27A1, HSD3B7, AKR1D1, and SLC27A5 genes in the X-ALD family. Outcomes: In the Polish family affected with AMN a dysregulation of the primary BA synthesis pathway was found. Lessons: We have demonstrated the coincidence of the adult form of X-ALD with abnormalities in BA synthesis. We suggest that decreased synthesis of BAs may be an additional dysfunction as a consequence of the ABCD1 c.659T>C, p.(Leu220Pro) mutation and may be further evidence that disturbed cholesterol metabolism is important in the pathology of ALD.

[4] Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

Authors: Catherine A. A. Lee, Hannah S. Seo, A. Armién, F. Bates, J. Tolar et al.
Year: 2018
Venue: Fluids and Barriers of the CNS
URL: https://www.semanticscholar.org/paper/0f5c432624d4ad49cfed766a22b6e9101d975e1f
DOI: 10.1186/s12987-018-0094-5
PMID: 29615068
PMCID: 5883398
Citations: 40
Summary: The finding that BBB integrity is decreased in X-linked adrenoleukodystrophy patients and can be rescued with block copolymers opens the door for the discovery of BBB-specific molecular markers that can indicate the onset of ccALD and has therapeutic implications for preventing the conversion.
Evidence snippets:
Snippet 1 (score: 0.557) > The molecular mechanisms responsible for the onset and progression of childhood cerebral adrenoleukodystrophy (ccALD) remain poorly understood. ccALD is one form of X-linked adrenoleukodystrophy (X-ALD), an inherited metabolic storage disorder affecting 1 in 17,000 individuals [1]. X-ALD is caused by mutations in the ABCD1 gene which codes for the ABCD1 protein [2]. ABCD1 is a peroxisomal transporter protein responsible for transporting very long-chain fatty acids (VLCFAs) from the cytosol into the peroxisome for subsequent beta-oxidation [3,4]. Mutation type and location are not predictive of phenotype, as the same ABCD1 mutation can lead to clinically distinct phenotypes [5][6][7][8][9]. A more frequent and less severe phenotype, adrenomyeloneuropathy (AMN), presents with demyelination in the long tracts of the spinal cord and progressive axonopathy, usually around the third or fourth decade of life. Heterozygous females will develop similar symptoms by age 60 [10][11][12]. ccALD, the most rapidly progressing phenotype, occurs in boys ages 2-12 and is characterized by sudden inflammatory demyelination in the brain and death within a few years [13,14]. ccALD affects about 40% of males with an ABCD1 mutation [15,16]. MRI observation of gadolinium enhancement in the brain remains the only method to detect this progression [17][18][19][20][21]. Infections or head trauma have been described as initiators of the conversion from AMN to ccALD, but typically no extrinsic factor can be identified [22][23][24]. Current treatment for ccALD includes hematopoietic cell transplant (HCT), but this must be performed at the earliest stages of the disease [12,14,25,26]. > Much attention has focused on VLCFAs in the search for alternative treatments.

[5] Pathophysiology of X-linked adrenoleukodystrophy☆

Authors: J. Berger, S. Forss-Petter, F. Eichler
Year: 2014
Venue: Biochimie
URL: https://www.semanticscholar.org/paper/470199defd6c7f0083788c24711f984c1f05e5bf
DOI: 10.1016/j.biochi.2013.11.023
PMID: 24316281
PMCID: 3988840
Citations: 186
Influential citations: 10
Summary: Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different and cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon–glial interactions seem pertinent to the dying-back axonopathy.
Evidence snippets:
Snippet 1 (score: 0.552) > Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype–phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35–40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon–glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the molecular mechanisms involved in these events is required for the development of urgently needed therapeutics.
Snippet 2 (score: 0.520) > Pathophysiology of X-linked adrenoleukodystrophy☆

[6] ABCD1 gene mutation in an Italian family with X-linkedadrenoleukodystrophy: case series

Authors: A. Mohn, N. Polidori, C. Aiello, C. Rizzo, C. Giannini et al.
Year: 2021
Venue: Endocrinology, Diabetes & Metabolism Case Reports
URL: https://www.semanticscholar.org/paper/866c83fe7f05f60c6b911d5aa815693a1b9a1d64
DOI: 10.1530/EDM-20-0125
PMID: 34013890
PMCID: 8185536
Citations: 6
Summary: A case series describing five family members affected by X-linked adrenoleukodystrophy caused by a novel mutation of the ABCD1 gene documented in a family group associated to an X-ALD possible Addison only phenotype is reported.
Evidence snippets:
Snippet 1 (score: 0.546) > Summary Adrenoleukodystrophy is a peroxisomal X-linked recessive disease caused by mutations in the ABCD1 gene, located on the X-chromosome (Xq28). Gene mutations in patient with adrenoleukodystrophy induce metabolic alterations characterized by impaired peroxisomal beta-oxidation and accumulation of very long chain fatty acid (VLCFA) in plasma and in all tissues. Although nutritional intervention associated with a various mixture of oil prevents the accumulation of VLCFA, to date no causal treatment is available. Therefore, haematopoietic stem cell transplantation (HSCT) and gene therapy are allowed only for very early stages of cerebral forms diagnosed during childhood.We reported a case series describing five family members affected by X-linked adrenoleukodystrophy caused by a novel mutation of the ABCD1 gene. Particularly, three brothers were affected while the sister and mother carried the mutation of the ABCD1 gene. In this family, the disease was diagnosed at different ages and with different clinical pictures highlighting the wide range of phenotypes related to this novel mutation. In addition, these characteristics stress the relevant role of early diagnosis to properly set a patient-based follow-up. Learning points We report a novel mutation in the ABCD1 gene documented in a family group associated to an X-ALD possible Addison only phenotype. All patients present just Addison disease but with different phenotypes despite the presence of the same mutations. Further follow-up is necessary to complete discuss the clinical development. The diagnosis of ALD needs to be included in the differential diagnosis in all patients with idiopathic PAI through accurate evaluation of VLCFA concentrations and genetic confirmation testing. Early diagnosis of neurological manifestation is important in order to refer timely to HSCT. Further follow-up of these family members is necessary to characterize the final phenotype associated with this new mutation.

[7] Brazilian Consensus Guidelines for Hematopoietic Stem Cell Transplantation - Inborn errors of metabolismo

Authors: A. Gomes, Adriana Mello Rodrigues, Juliana Folloni Fernandes, L. Daudt, C. Bonfim
Year: 2021
Venue: JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY
URL: https://www.semanticscholar.org/paper/41f23a1ce730f36f34164f398c61ad280675f292
DOI: 10.46765/2675-374x.2021v2n4p126
Citations: 1
Summary: Brazilian Group for Pediatric Bone Marrow Transplantation and Cellular Therapy (SBTMO) provides a review of HSCT indications in inborn errors of metabolism (IEM), based on correcting the decreases enzymes by the donor cells within and outside the intravascular compartment.
Evidence snippets:
Snippet 1 (score: 0.534) > X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by cerebral demyelination, adrenal insufficiency and progressive neurologic deterioration. The ALD gene encodes the ABCD1 protein which is involved in transport of fatty acyl coenzyme A substrates or their cofactors into peroxisomes. Its metabolic hallmark is the accumulation of very long chain fatty acids (VLCFA) in tissues and plasma, due to impaired transport and beta-oxidation of these fatty acids in peroxisomes. However, it has no effect in patients with established neurologic deficits, as brain levels of VLCFA are unchanged by the treatment 13 . > Patients with X-Linked ADL may present with 6 forms of the disease. The cerebral form affects approximately 40-60% of patients and is characterized by cognitive deficits followed by progressive demyelination of the CNS and evolution to disability, demen-tia, neurovegetative state and death within a few months to several years from diagnosis. A complete evaluation of a boy with cerebral X-ALD includes a thorough neurologic examination, comprehensive neuropsychological assessment with IQ and an MRI of the brain with and without contrast (gadolinium) with MRI severity score determination, referred to as the Loes score. The predominant pattern of demyelination seen by brain MRI is posterior in 80-85% of cases. Although neurologic deterioration occurs in all boys with the cerebral form, 40% of female heterozygous carriers exhibit mild-to-moderate non-cerebral signs of the disease 13 . > HSCT is indicated in the progressive cerebral form, at an early stage, aiming to prevent the progression of cerebral demyelination. The patient should undergo clinical assessment of neurological status (IQ >80) and MRI (Loes score >1 and <9) before the procedure. The neurologic benefits of HSCT in X-linked adrenoleukodystrophy are mediated by the replacement of brain microglial cells derived from donor bone marrow myeloid cells.

[8] Genomic Profiling Identifies Novel Mutations and SNPs in ABCD1 Gene: A Molecular, Biochemical and Clinical Analysis of X-ALD Cases in India

Authors: Neeraj Kumar, K. Taneja, V. Kalra, M. Behari, S. Aneja et al.
Year: 2011
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/e169937fcb3ec3b596c0d37fb32609c787049664
DOI: 10.1371/journal.pone.0025094
PMID: 21966424
PMCID: 3178599
Citations: 22
Influential citations: 2
Summary: This is the first preliminary comprehensive study in Indian population that identified novel mutations and SNPs in a relatively large group and enhances the knowledge of the causative mutations of X-ald that grants holistic base to develop effective medicine against X-ALD.
Evidence snippets:
Snippet 1 (score: 0.531) > X-linked adrenoleukodystrophy (X-ALD; OMIM # 300100) is one of the most frequent monogenic inherited peroxisomal neurodegenerative disorders. It affects the cerebral white matter, peripheral nerves, adrenal cortex and testis [1]. It is a recessive, usually male lethal, serious and progressive genetic disorder characterized by abnormal accumulation of saturated very long chain fatty acids (VLCFA) in body fluids and affected tissues, most notably in the brain and adrenal cortex due to an impaired boxidation in peroxisomes [1][2][3][4]. The frequency of X-ALD in USA is 1:21,000 in males [5]. Seven different phenotypes have been described for male and five for female patients [6]. The more frequent male clinical phenotypes are cerebral form and adrenomyeloneuropathy (AMN). The cerebral forms viz. childhood, adolescent, and adult are characterized by intellectual, behavioral, cognitive, visual, gait disturbances associated with a rapid neurological progression, inflammatory reaction in the cerebral white matter and increased expression of cytokines which may involve autoimmune mechanisms [7,8]. AMN, present only in adults, is characterized by gait, sensory, autonomic disturbances with slower progression, inflammatory response absent or mild and may affect the spinal cord and peripheral nerves. About 35% of AMN patients develop cerebral involvement at a later stage [6,7]. Other less frequent phenotypes include asymptomatic, olivoponto-cerebellar (OPC) and Addison-only disorders (6). These different phenotypes might appear within the same family due to an identical ABCD1 gene mutation [9][10][11][12]24]. Additional genetic or environmental/epigenetic/stochastic factors have been suggested as the modulator of clinical phenotypes due to lack of any established genotype-phenotype correlation [13][14][15].

[9] Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

Authors: Pedro de Vasconcelos, J. Lacerda
Year: 2022
Venue: Frontiers in Cellular Neuroscience
URL: https://www.semanticscholar.org/paper/68bf3ae01f47f1a62cae34a7e232d89b88859913
DOI: 10.3389/fncel.2022.895511
PMID: 35693884
PMCID: 9178264
Citations: 23
Influential citations: 1
Summary: This review focuses on the mechanisms of brain repair resulting from HSCT and gene therapy in Inborn Errors of Metabolism, a large spectrum of multisystem disorders characterized by congenital deficiencies in enzymes involved in metabolic pathways.
Evidence snippets:
Snippet 1 (score: 0.527) > X-Linked Adrenoleukodystrophy (ALD) is characterized by mutations in the ABCD1 gene that encodes adrenoleukodystrophy protein, a membrane transporter of substrates from the cytosol to the peroxisome. As a consequence of absent adrenoleukodystrophy protein, there is defective transportation of very long-chain fatty acids to the peroxisome for oxidative degradation, resulting in CNS and adrenal tissue accumulation (Moser, 1997). Four major presentations of ALD have been defined: asymptomatic, adrenal failure, adrenomyeloneuropathy and cerebral inflammatory disease. Occurring in 40% of patients during childhood or adolescence, Cerebral ALD (CALD) is the most severe disease phenotype and is associated with progressive neurological impairment and early mortality if left untreated (Moser et al., 1992;Tran et al., 2017). Affected boys develop normally until 4-12 years of age, then cerebral demyelination starts and progresses slowly over 1-3 years with mild symptomatology. After this initial period, a devastating clinical course begins. Rapid cerebral inflammatory demyelination ensues, BBB is disrupted, and peripheral innate immune cells migrate to the active edges of demyelinating lesions. Within 2-4 years of the first symptoms, affected patients enter a vegetative state associated with a dismal prognosis (Eichler et al., 2008). > The pathogenesis of CALD is defined initially by two events triggered by selective accumulation of substrate in specific brain structures: (1) destabilization of myelin sheaths and demyelination; (2) direct dysregulation of oxidative phosphorylation and mitochondrial function of neuroaxons. These processes are followed by a rapidly progressive inflammatory demyelination state characterized by invasion of myelin debris-laden macrophages and BBB dysfunction (Eichler et al., 2008;Lund et al., 2012;López-Erauskin et al., 2013;Weinhofer et al., 2018).

[10] The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis

Authors: Xiao-ming Wang, Wing Yan Yik, Peilin Zhang, W. Lu, Patricia K Dranchak et al.
Year: 2012
Venue: Stem Cell Research & Therapy
URL: https://www.semanticscholar.org/paper/3ae3af2b37ab12d0bb074c62596f613f5d571177
DOI: 10.1186/scrt130
PMID: 23036268
PMCID: 3580430
Citations: 32
Summary: Normal ABCD1 gene function is not required for reprogramming skin fibroblasts into iPSCs or maintaining pluripotency, and these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes.
Evidence snippets:
Snippet 1 (score: 0.524) > X-linked adrenoleukodystrophy (X-ALD) is a complex disorder caused by mutations in the ABCD1 gene that encodes an integral peroxisome membrane protein belonging to the ATP-binding cassette transporter superfamily [1][2][3][4]. X-ALD primarily affects the nervous system, adrenal cortex and testes with highly variable clinical presentations that are influenced by modifier genes and the environment [2,3]. Males with ABCD1 mutations develop childhood cerebral ALD (CCALD) about 33% of the time and adult onset adrenomyeloneuropathy (AMN) about 45% of the time [2,3]. CCALD patients typically show symptoms between five and nine years of age with rapid cerebral demyelination and adrenocortical atrophy. Within a few years of onset, they suffer dementia and progressive neurological deficits that eventually lead to death. In contrast, AMN patients show a later onset of disease (20 to 40 years of age) and present with adrenal insufficiency, a distal axonopathy in the spinal cord and peripheral neuropathy that results in progressive spastic paraparesis with debilitating end stage disease [2,3]. Approximately 10% of hemizygotes develop primary adrenocortical insufficiency (Addison's disease) with no evidence of nervous system dysfunction [2,3]. Disease prognosis is challenging since mutations do not correlate with clinical phenotypes [5] and male siblings with the same ABCD1 mutation, including monozygotic male twins [6,7], can have dramatically different clinical presentations [8]. Although hemizygotes typically show the most severe clinical manifestations of disease, about half of female ABCD1 mutation carriers develop AMN-like symptoms later in life [2,3]. > The molecular mechanisms underlying the inflammatory brain demyelination found in CCALD patients are not fully understood. It has been hypothesized to be related to the accumulation of saturated very long chain fatty acids (sVLCFAs) in specific central nervous system (CNS) cell types (for example, oligodendrocytes and microglial cells) and

[11] Cerebrospinal Fluid Matrix Metalloproteinases Are Elevated in Cerebral Adrenoleukodystrophy and Correlate with MRI Severity and Neurologic Dysfunction

Authors: Kathryn A. Thibert, G. Raymond, D. Nascene, W. Miller, J. Tolar et al.
Year: 2012
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/b32e8098ec71a416985b2155a601647d9f7a4a68
DOI: 10.1371/journal.pone.0050430
PMID: 23185624
PMCID: 3503955
Citations: 34
Summary: MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier and appear to directly correlate to radiographic and clinical neurologic severity.
Evidence snippets:
Snippet 1 (score: 0.511) > X-linked adrenoleukodystrophy (ALD) is a neurometabolic disease that results from mutations in ABCD1, the gene that encodes for a peroxisomal transporter of very long chain fatty acid (VLCFA) and subsequently disrupts their metabolism and results in the accumulation of these compounds in all tissues. [1]. ALD predominantly affects the adrenal cortex, testes, and nervous system. The nervous system manifestations are variable. Cerebral disease is the most common neurologic presentation in childhood. Adrenomyeloneuropathy is an adult presentation and is characterized by involvement of the long tracts of the spinal cord. However, adult men may also develop cerebral disease. It is important to point out that while ALD is characterized by the accumulation of VLCFA, only 35% of individuals at risk will develop cerebral disease in childhood and no correlation has been observed between the accumulation of the fatty acids in serum and the clinical phenotype for ALD [1]. There is also no known correlation between mutation and phenotypes, making it difficult to predict the presentation or progression of the disease. > Cerebral ALD is characterized by central inflammatory demyelination [2]. The five-year survival rate after first appearance of clinical symptoms of cerebral inflammation is 59% [3]. In boys with an ABCD1 mutation, there is currently no reliable way to predict who will develop neuroinflammation or when neuroinflammation may occur. There are very few therapeutic options once neuroinflammation occurs. Treatment with Lorenzo's oil (glycerol trioleate and glycerol trierucate) combined with a VLCFA-low diet normalizes the concentration of VLCFA and may delay neurologic disease in those predestined to develop it, but it does not slow the progress of neurological symptoms once they have begun [4]. Hematopoietic cell transplant (HCT) is the only way to reduce the cerebral inflammation and arrest the demyelination process once it has started [2], although the mechanism underlying the disease attenuation remains unknown.

[12] Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

Authors: Paul J. Orchard, Troy C. Lund, Wes P. Miller, Steven M. Rothman, Gerald V. Raymond et al.
Year: 2011
Venue: Journal of Neuroinflammation
URL: https://www.semanticscholar.org/paper/4421d817f113af080aef7f8216acdf0980f46597
DOI: 10.1186/1742-2094-8-144
PMID: 22014002
PMCID: 3236018
Citations: 24
Influential citations: 2
Summary: Elevation of chitotriosidase activity in patients with active C-ALD is confirmed and these levels predict prognosis of patients with C-ALD undergoing transplantation, suggesting that these levels predict prognosis of patients with C-ALD undergoing transplantation.
Evidence snippets:
Snippet 1 (score: 0.505) > Adrenoleukodystrophy (ALD) is an X-linked, peroxisomal disorder of very long chain fatty acid (VLCFA) metabolism, resulting in the accumulation of VLCFA in the adrenal gland, testes and brain. The disease frequency is approximately 1 in 17,000 males, and has been reported to be similar in distribution across ethnic and racial groups [1,2]. The capacity to metabolize VLCFA, a reaction that normally takes place in the peroxisome, is impaired in patients with X-ALD due to defects in the ABCD1 gene encoding a peroxisomal membrane protein designated ALDp. A large number of genetic mutations have been identified as causing disease, and there is substantial clinical variability within kindreds despite a conserved genotype [2,3]. > The most severe phenotype of ALD is the cerebral form (C-ALD), which is observed in approximately 40% of children affected by ALD. The median age of clinical onset is 7 years. A characteristic finding associated with C-ALD is inflammation of the white matter of the brain, with changes suggesting active oxidative damage thought to be due to the inflammatory process [4]. The disease is associated with progressive demyelination, and once initiated, generally leads to a vegetative state or death within several years of onset. The only available therapy shown to provide long-term stabilization of C-ALD is allogeneic hematopoietic stem cell transplantation, although there is an interest in the development of gene therapy [5]. At this time, the mechanism by which transplantation arrests the disease process is incompletely understood. It is thought to be due, at least in part, to modulation of the neuroinflammatory process. Given the risks associated with transplantation, the current standard of care for neurologically asymptomatic patients is to monitor them prospectively for cerebral involvement by scheduled MRI imaging. If white matter changes with gadolinium enhancement are observed, providing evidence of active inflammation and progression, transplantation should be expediently performed. > Currently, there is no clear means of determining which patients with ALD are likely to develop C-ALD. In addition, for patients with symptoma

[13] From gene to therapy: a review of deciphering the role of ABCD1 in combating X-Linked adrenoleukodystrophy

Authors: Xinxin Zuo, Zeyu Chen
Year: 2024
Venue: Lipids in Health and Disease
URL: https://www.semanticscholar.org/paper/04fae1a7cb7972f61cd1653a6371881ce6491041
DOI: 10.1186/s12944-024-02361-0
PMID: 39529100
PMCID: 11552335
Citations: 8
Summary: The need to fully elucidate the pathogenesis of X-ALD is emphasized, and the importance of international collaboration to enhance systematic data collection and advance biomarker discovery is highlighted, ultimately improving patient outcomes with X-ALD.
Evidence snippets:
Snippet 1 (score: 0.502) > X-linked adrenoleukodystrophy (X-ALD) is a genetically mediated disorder that results in progressive deterioration of the central and peripheral nervous systems and the adrenal cortex. It predominantly affects male patients and is estimated to be present in approximately 1 in 17,000 newborns [1]. X-ALD manifests in three phenotypes, which vary according to the age of onset and the severity of symptoms: cerebral ALD (CALD), which AMN symptoms usually begin to appear in men in their 30s and 40s, whereas AMN clinical signs may appear in women after the age of 60 [4]. AMN is categorized into "AMN pure" and "AMN cerebral" types [5]. In AMN pure, pathology is confined to the spinal cord, manifesting as ambulatory disturbances and urinary dysfunction. AMN cerebral exhibits the spinal cord involvements seen in AMN pure and additional cerebral inflammatory symptoms. The mechanisms underlying the transition from AMN pure to AMN cerebral are not clearly defined. > X-ALD results from mutations in ABCD1, which encodes the ATP-binding cassette (ABC) subfamily D member 1 (ABCD1), a 745-amino-acid peroxisomal transmembrane protein [6]. ABCD1 is crucial for transporting very-long-chain fatty acids (VLCFAs) into peroxisomes, where they undergo β-oxidation [6]. In X-ALD, mutations in ABCD1 impair this process, resulting in the accumulation of VLCFAs in the blood and in tissues, such as adrenal gland, testicular, and nervous system tissues. The most common diagnostic methods involve measuring the total concentration of the VLCFA C26:0 or the ratios of C26:0 to C22:0 and C24:0 to C22:0, as concentrations of C22:0 typically remain stable in patients with X-ALD [7]. However, despite extensive research, the exact correlation between specific gene mutations and symptoms remains undetermined, and VLCFA concentrations are not reliably predictive of disease-specific symptoms such as adrenal insufficiency or neurological decline.

[14] IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy.

Authors: P. Parasar, N. Kaur, J. Singh
Year: 2023
Venue: Journal of biotechnology and biomedicine
URL: https://www.semanticscholar.org/paper/6fab52a715449279623a980a8025e71b8298d32a
DOI: 10.26502/jbb.2642-91280091
PMID: 38077449
Citations: 7
Summary: X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder caused by pathogenic variants in the ABCD1 gene, leading to accumulation of saturated very long chain fatty acids (VLCFA) in body fluids and tissues including brain and spinal cord. In the absence of a clear genotype-phenotype correlation the molecular mechanisms of the fatal cerebral adrenoleukodystrophy (cALD) and the milder adrenomyeloneuropathy (AMN) phenotypes remain unknown. Given our previous evidence of role of a...
Evidence snippets:
Snippet 1 (score: 0.502) > X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disease due to a defective ABCD1 gene encoding the peroxisomal ABC half-transporter ABCD1 or adrenoleukodystrophy (ALD) protein. ABCD1 mutations impair β-oxidation of fatty acids, leading to accumulation of very long chain fatty acids (VLCFAs), predominantly C26:0 in blood and tissues, which adversely affects the brain, spinal cord, and adrenals [1]. A total of 1000 unique variants of ABCD1 in >3400 cases ABCD1 variants have been reported in X-ALD; however, no correlation of genotype to clinical phenotype exists (https://adrenoleukodystrophy.info/) [2]. X-ALD phenotypes include rapidly progressive inflammatory demyelinating cerebral adrenoleukodystrophy (cALD), milder adult-onset forms, adrenomyeloneuropathy (AMN. Approximately 35% of affected males develop cALD before reaching 12 years of age. Without early intervention, most patients with cALD die within a decade after diagnosis. AMN is a gradually developing phenotype, first affecting males with dysfunctional ABCD1 at age 20-30 years manifesting with gait disturbances and bladder dysfunction. About 30% of patients with AMN develop cerebral inflammation, ultimately progressing to the fatal cALD form in adulthood [1,2]. Human astrocytes are the major cell population in the central nervous system and play a substantial role in X-ALD pathogenesis, and the peroxisomal ABCD1 protein plays a role in the murine astrocyte inflammatory response [3]. We previously documented that loss of adenosine monophosphate-activated protein kinase α1 (AMPKα1) in patients with cALD was associated with a higher inflammatory profile in patient-derived cells [4][5][6]; however, the underlying definitive mechanisms of phenotypic variability and differential inflammatory responses between AMN and cALD phenotypes remain unknown.

[15] Pain Study in X-Linked Adrenoleukodystrophy in Males and Females

Authors: V. Bachiocco, M. Cappa, A. Petroni, E. Salsano, C. Bizzarri et al.
Year: 2021
Venue: Pain and Therapy
URL: https://www.semanticscholar.org/paper/32acab0b52b16acea6ab44581f0bf426e9872a2e
DOI: 10.1007/s40122-021-00245-0
PMID: 33609269
PMCID: 8119579
Citations: 5
Summary: The study of pain and of the sensory profile appears to indicate a difference in the mechanisms underlying the AMN/cAMN/ cALD and AD clinical forms and in the treatment of the respective generated pain types.
Evidence snippets:
Snippet 1 (score: 0.500) > Adrenoleukodystrophy (ALD) is an X-linked inherited metabolic disease caused by mutations in the ATP-binding cassette (ABC) transporter subfamily D member 1 gene (ABCD1) which encodes for a peroxisomal transmembrane protein involved in the transport of very long chain fatty acids (VLCFA) from cytosol into peroxisomes, where they undergo b-oxidation [1,2]. Abnormal accumulation of VLCFA is ubiquitous, but the nervous system, adrenal cortex and testis are mainly affected [1,3]. The excess of VLCFA and the development of molecular and metabolic alterations cause different functional impairment in the tissues, and the downstream mechanisms dictating the signature and severity of the disease are still largely unclear [4][5][6][7]. The clinical phenotype is heterogeneous, although three major variants have been described. Addison's disease only (AD) is characterized by decreased cortisol production and release, and thus by adrenal insufficiency [8,9]. Adrenomyeloneuropathy (AMN) involves a progressive axonopathy affecting sensory ascending and motor descending spinal tracts as well as peripheral nerves, which causes sensory and motor disturbances [5,6,8]. Cerebral adrenoleukodystrophy (cALD), or cerebral adrenomyeloneuropathy (cAMN), is marked by myelin destabilization and serious neuroinflammation [1,5,6,8], giving rise to severe cognitive, behavioral and neurological dysfunctions. Sixty-six percent of AMN patients present adrenal involvement [8], while 35% [10,11] progress towards an overt cerebral inflammatory form. > Signs and symptoms of the disease have been described in males and also in females, so-called carriers. Nevertheless, depending on the studies, 50% or more of such women present some neurological anomaly, 57% manifest a peripheral neuropathy and 63% develop a late progressive myelopathy [12,13]. Both large and small nerve fiber dysfunction has been described in AMN-like females [8,14] and in AMN males [15][16][17].

[16] A Novel Missense Variant of the ABCD1 Gene in X‐Linked Adrenoleukodystrophy in Chinese Family

Authors: Hongxia Fu, Lu Han, Xianhong Liu, Bin He, Pei He et al.
Year: 2025
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/9845caa206d1f56e544705eac382ab551343dd04
DOI: 10.1002/mgg3.70148
PMID: 41041882
PMCID: 12492069
Summary: A novel ABCD1 variant is identified in a Chinese pedigree affected by X‐linked adrenoleukodystrophy and likely constitutes the genetic basis of the disease phenotype in this family.
Evidence snippets:
Snippet 1 (score: 0.497) > X-linked adrenoleukodystrophy (X-ALD, OMIM: 300100) is a devastating inherited disorder predominantly affecting males, characterized by progressive demyelination and axonal degeneration in the nervous system and adrenal insufficiency. With a global prevalence of approximately 1 in 17,000 newborns (Mukherjee et al. 2024), its clinical heterogeneity poses significant diagnostic and prognostic challenges. The disease spectrum ranges from the rapidly fatal childhood cerebral form (CCALD, ~35% of cases) to the chronic adrenomyeloneuropathy (AMN, ~60%) and Addison-like presentations (Baker et al. 2022;Parasar et al. 2024;Zuo and Chen 2024). This profound variability, particularly the unpredictable progression to lethal cerebral involvement, underscores the critical need for better predictors of disease course and targets for intervention. > The core molecular defect lies in pathogenic variants of the ABCD1 gene, which encodes the peroxisomal membrane protein adrenoleukodystrophy protein (ALDP). ALDP functions as a homodimer essential for transporting VLCFA into peroxisomes for β-oxidation (Chen et al. 2022;Schleker et al. 2022). ABCD1 mutations disrupt this process, leading to toxic VLCFA accumulation primarily in the adrenal cortex, testes, and neural tissues, driving disease pathogenesis (Chen et al. 2022). > Despite the identification of over 3700 distinct ABCD1 variants cataloged in the X-ALD Mutation Database (Liu et al. 2022), a fundamental gap persists in understanding the mechanistic relationship between the spectrum of ABCD1 mutations, particularly those disrupting transmembrane and ATP-binding domains critical for transporter function (Jia et al. 2022;Schleker et al. 2022), and the extreme clinical heterogeneity observed in X-ALD. This genotype-phenotype discordance severely hinders accurate prognosis and personalized management strategies for affected individuals and families. > In this study, we identified a novel ABCD1 variant (c.773T>G).

[17] Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients

Authors: W. Miller, L. F. Mantovani, J. Muzic, J. Rykken, R. Gawande et al.
Year: 2016
Venue: American Journal of Neuroradiology
URL: https://www.semanticscholar.org/paper/f6a2042d09199bf0e5695cf8cf8edccbe3a01e20
DOI: 10.3174/ajnr.A4500
PMID: 26427835
Citations: 36
Influential citations: 1
Summary: Gadolinium enhancement intensity on brain MR imaging can be scored simply and reproducibly for cerebral adrenoleukodystrophy and in boys with higher risk cerebral disease, the enhancement score itself predicts neurologic outcome following treatment.
Evidence snippets:
Snippet 1 (score: 0.495) > order affecting approximately 1 in 21,000 males. Mediated by elevated concentrations of very long chain fatty acids, the disease may manifest as central nervous system demyelination, primary hypoadrenalism, and/or primary hypogonadism. The disease results from pathogenic mutations in the peroxisomal transporter ABCD1 gene, but genotype does not predict the presentation, and different presentations may occur within the same family. 1, 2 In 35% of affected males, cerebral involvement (cerebral adrenoleukodystrophy [cALD]) begins in childhood. This devastating phenotype is characterized by rapidly progressive central nervous demyelination and, if untreated, usually death within years of onset of clinical signs and symptoms. 3 Postmortem analyses of affected brains have implicated mononuclear inflammatory mechanisms. [4][5][6] Radiographic changes generally precede clinical neurologic disease by several years in childhood cALD and are characterized by symmetric, expanding white matter lesions. 7 Consistent with known neuroinflammatory histopathology, gadolinium enhancement is typically observed near the leading edge of active demyelination and, when present, strongly predicts dis-ease progression. 8,9 The cALD brain MR imaging severity scale of Loes et al 10 is commonly used to quantify radiographic disease burden in adrenoleukodystrophy. Increasing Loes scores denote accumulating white matter disease and atrophy in defined neuroanatomic or functional regions: periventricular/subcortical areas (parieto-occipital, anterior-temporal, and frontal), corpus callosum, visual and auditory pathways, frontopontine-corticospinal projection fibers (internal capsule and brain stem), basal ganglia, cerebellum, and anterior thalamus. For patients with ALD with no cerebral involvement, the Loes score is by definition zero, while maximal cerebral involvement on the scale (Loes ϭ 34) correlates with profound neurologic impairment. 10 Although experimental gene therapy trials are currently underway, allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard therapy to arrest cerebral disease progression in cALD

[18] A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers

Authors: M. Cappa, C. Bizzarri, A. Petroni, G. Carta, L. Cordeddu et al.
Year: 2011
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/8f79e6f4a6ecbb69f38f265f9bf95a94c244f05f
DOI: 10.1007/s10545-011-9432-3
PMID: 22189598
PMCID: 3432215
Citations: 41
Influential citations: 1
Summary: The data suggest that the synergic activity of CLA and LO, by enhancing peroxisomal beta-oxidation and preventing 26:0 formation, improves the somatosensory evoked potentials and reduces neuroinflammation.
Evidence snippets:
Snippet 1 (score: 0.495) > X−linked adrenoleukodystrophy (ALD) is an inherited demyelinating disorder. The disease is characterized by an abnormal accumulation of very long chain fatty acids (VLCFA), owing to a defect in VLCFA peroxisomal beta-oxidation. The gene responsible for ALD was cloned and originally termed adrenoleukodystrophy gene. This gene encodes a 745 amino acid peroxisomal transmembrane protein (ALDP) with the general structure of an ATP-binding cassette transporter (Mosser et al. 1993). The prevalence of the disease is 0.5 to 3.3 in 100,000 males (Heim et al. 1997;Kirk et al. 1998). There are seven distinct clinical phenotypes described in males, ranging from the more severe cerebral forms, to asymptomatic individuals or isolated adrenal insufficiency, without involvement of the central nervous system. Approximately 50% of women who are heterozygous for ALD develop an adrenomyeloneuropathy (AMN)-like syndrome, a higher proportion than what had been recognized in the past. The mean age at the onset of symptoms in heterozygous females (37±14.6 years, range 32-73 years) is greater than in men with AMN (28±9 years), clinical symptoms are milder and progression is slower. Cerebral and adrenal involvement are rare in females (Moser et al. 1991;Restuccia et al. 1997). > All the cerebral forms are inflammatory forms, associated with a rapidly progressive intensely inflammatory myelinopathy, that usually begins in the parietooccipital regions (Schaumburg et al. 1975;Ito et al. 2001) and may involve autoimmune mechanisms (Ito et al. 2001). > The accumulation of VLCFA in different tissues, including the brain, has been so far believed to be the major cause of ALD. This hypothesis stems from the evidence that an increase of 26:0 intercalated into the membrane (Ho et al. 1995) may account for the demyelination and may also increase immunoreactivity (Baes and Aubourg 2009).

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X-linked cerebral adrenoleukodystrophy

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of X-linked cerebral adrenoleukodystrophy. Core disease mechanisms, molecular...

Relevant Papers

[1] The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

[2] X-linked Adrenoleukodystrophy in a 20-Year-Old Male With an ABCD1 Gene Mutation: First Case From Pakistan

[3] Case report of dysregulation of primary bile acid synthesis in a family with X-linked adrenoleukodystrophy

[4] Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

[5] Pathophysiology of X-linked adrenoleukodystrophy☆

[6] ABCD1 gene mutation in an Italian family with X-linkedadrenoleukodystrophy: case series

[7] Brazilian Consensus Guidelines for Hematopoietic Stem Cell Transplantation - Inborn errors of metabolismo

[8] Genomic Profiling Identifies Novel Mutations and SNPs in ABCD1 Gene: A Molecular, Biochemical and Clinical Analysis of X-ALD Cases in India

[9] Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

[10] The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis

[11] Cerebrospinal Fluid Matrix Metalloproteinases Are Elevated in Cerebral Adrenoleukodystrophy and Correlate with MRI Severity and Neurologic Dysfunction

[12] Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

[13] From gene to therapy: a review of deciphering the role of ABCD1 in combating X-Linked adrenoleukodystrophy

[14] IPSC-Derived Astrocytes to Model Neuroinflammatory and Metabolic Responses in X-linked Adrenoleukodystrophy.

[15] Pain Study in X-Linked Adrenoleukodystrophy in Males and Females

[16] A Novel Missense Variant of the ABCD1 Gene in X‐Linked Adrenoleukodystrophy in Chinese Family

[17] Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of Outcome following Transplantation in Higher Risk Patients

[18] A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers

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