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Inheritance

1

X-linked recessive inheritance HP:0001419

Classic adrenoleukodystrophy is inherited as an X-linked recessive disorder due to pathogenic ABCD1 variants.

X-linked recessive inheritance

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Subtypes

3

Childhood cerebral adrenoleukodystrophy MONDO:0010247

The inflammatory cerebral form marked by rapidly progressive white-matter demyelination and the main subtype considered for early HSCT. Anchored to MONDO:0010247, the cerebral child class of the ABCD1 umbrella (MONDO:0018544); this subtype carries the cerebral-ALD mechanism that was formerly duplicated in a standalone X-linked cerebral ALD entry, which was removed in favor of this single ABCD1 pathograph (#4179).

Adrenomyeloneuropathy MONDO:0015339

The adult spinal cord and peripheral nerve-predominant form of adrenoleukodystrophy.

Addison-only adrenoleukodystrophy

A presentation with primary adrenal insufficiency before overt neurologic disease. No dedicated MONDO leaf class exists for the Addison-only ALD form, so no subtype_term is asserted here (the autoimmune-Addison class MONDO:0100480 is a distinct disease and must not be used).

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Mechanistic Hypotheses

1

Canonical ABCD1 / VLCFA Accumulation / Demyelination & Adrenal Insufficiency Model

canonical_abcd1_vlcfa_demyelination_adrenal_model CANONICAL

Evidence balance 3 support

X-linked adrenoleukodystrophy (X-ALD) is caused by loss-of-function variants in ABCD1 on Xq28 encoding the peroxisomal membrane transporter ALDP, which imports very-long-chain fatty acid (VLCFA) CoA-esters into the peroxisome for β-oxidation. Loss of ABCD1 function disables peroxisomal β-oxidation of saturated VLCFAs (C24:0, C26:0) and produces their pathological accumulation in plasma, adrenal cortex, Leydig cells, oligodendrocytes, and CNS myelin. VLCFA accumulation drives mitochondrial dysfunction, oxidative stress, microglial activation, and a neuroinflammatory cerebral demyelination program, alongside adrenocortical apoptosis producing primary adrenal insufficiency. Hematopoietic stem-cell transplantation and lentiviral gene therapy (elivaldogene autotemcel) halt cerebral disease progression in early-stage childhood cerebral ALD, corroborating the ABCD1-loss / VLCFA-accumulation / neuroinflammatory-demyelination axis as the canonical pathogenic mechanism.

Retained as CANONICAL with PARTIALLY SUPPORTED qualification (upstream definitive, downstream mechanistically incomplete). The 2026 openscientist hypothesis-search report (kb/hypotheses/adrenoleukodystrophy/canonical_abcd1_vlcfa_demyelination_adrenal_model) confirms 18 findings from 120 papers. Upstream biochemistry is definitively established: cryo-EM ABCD1 structure, VLCFA-CoA substrate recognition, impaired peroxisomal β-oxidation, and ELOVL1-amplified VLCFA accumulation. Lentiviral gene therapy (eli-cel/elivaldogene autotemcel; PMID:39383459) and allogeneic HSCT provide therapeutic proof-of-concept by halting cerebral disease via hematopoietic ABCD1 restoration. Three critical downstream refinements limit the model's explanatory power: (1) VLCFA accumulation is necessary but not sufficient for cerebral inflammatory demyelination — all patients accumulate VLCFA but only 35–40% of males develop cerebral ALD, with no genotype-phenotype correlation, indicating unknown modifier genes and environmental/stochastic factors determine phenotypic conversion; (2) no animal model spontaneously develops cerebral demyelination despite VLCFA accumulation, indicating VLCFA alone cannot drive the inflammatory cerebral phenotype; (3) adrenal insufficiency operates through a pathway DISTINCT from the neuroinflammatory cascade — HSCT/ gene therapy fail to correct adrenal dysfunction; first therapeutic adrenal rescue achieved through 2-hydroxypropyl-β- cyclodextrin (HPCD), suggesting lysosomal cholesterol trapping rather than VLCFA toxicity drives adrenocortical apoptosis. Six downstream mechanisms converge on tissue damage: mitochondrial dysfunction / oxidative stress, NLRP3 inflammasome via 25-hydroxycholesterol, CD1-mediated lipid antigen presentation to CD8 T cells, macrophage CD36/JNK priming, ER-stress/UPR activation, and emerging ferroptosis. Only saturated VLCFAs are specifically toxic. Plasma neurofilament light chain (NfL) is validated as a prognostic biomarker for cerebral disease onset and treatment response.

Deep research

OpenScientist citations 54 citations 2026-05-24T00:04:13.665822

Show evidence (3 references)

PMID:32101828 SUPPORT Human Clinical

"Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene."

Canonical mechanism reference used as the seed for the hypothesis-search deep-research run.

PMID:25999754 SUPPORT Other

"the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD"

Substantiates the qualification recorded in this hypothesis's notes that the ABCD1 genotype does not determine which phenotype develops, so modifier genes and environmental factors must contribute.

PMID:34716609 SUPPORT Model Organism

"cerebral invasion of leukocytes and demyelination were not observed in any animal model for X-ALD, reflecting upon pathological processes that are yet to be discovered"

Substantiates the qualification recorded in this hypothesis's notes that VLCFA accumulation alone does not produce the cerebral inflammatory phenotype, since every published model reproduces the biochemistry without the cerebral lesion.

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Discussions and Knowledge Gaps

4

What determines which males carrying an ABCD1 variant convert to the cerebral inflammatory phenotype, given that every patient accumulates VLCFA and the ABCD1 genotype does not predict the outcome?

KNOWLEDGE GAP OPEN ald_cerebral_conversion_trigger

Attached to

pathophysiology#Very long-chain fatty acid accumulation pathophysiology#Inflammatory cerebral demyelination mechanistic_hypotheses#canonical_abcd1_vlcfa_demyelination_adrenal_model

This is the central unresolved question in X-ALD and the reason the canonical model is annotated as necessary but not sufficient downstream. The genotype carries no phenotype information, so modifier genes, environmental exposure, or stochastic factors must decide conversion, and none has been identified: candidate-gene work on the CD1 locus, other ABCD paralogues, and methionine metabolism has not replicated, and no genome-wide association study has been published. The therapeutic corollary is that normalizing plasma VLCFA is not by itself sufficient, as the Lorenzo's oil visual-pathway trial showed. Without the trigger, prevention is impossible and management stays reactive MRI surveillance. Note that the conversion fraction itself is cohort- and age-dependent: reviews commonly quote 35 to 40 percent of males while the Danish national cohort reports 44 percent by age 60, so no single figure should be curated as settled.

Proposed experiments

Phenotype-stratified ALD modifier GWAS and EWAS

exp_ald_modifier_gwas_ewas

Assemble newborn-screening-identified and clinically phenotyped males across an international consortium, stratify by cerebral ALD versus adrenomyeloneuropathy versus asymptomatic status at a fixed age threshold, and run genome-wide genotyping with imputation plus epigenome-wide methylation on matched samples. A null result at adequate power would itself be informative, shifting weight toward stochastic or environmental determination.

Show evidence (3 references)

PMID:25999754 SUPPORT Other

"Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course."

A review of the modifier-gene literature concluding that the determinants of phenotype remain unidentified despite repeated searches.

PMID:8338341 SUPPORT Human Clinical

"there was no evidence that reduction of VLCFA levels improved or retarded visual pathway demyelination"

Lowering plasma VLCFA markedly, without arresting demyelination, is direct clinical evidence that the VLCFA level is not the proximate determinant of neurological progression once disease is established.

PMID:41166774 SUPPORT Human Clinical

"By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 % had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency."

A genetically ascertained national cohort quantifies the incomplete and divergent penetrance of the three arms, which is the observation the gap is about.

Does any available animal model reproduce the cerebral inflammatory demyelination of childhood cerebral ALD without artificial immune provocation, and what does the failure to do so say about the missing step?

HUMAN MODEL MISMATCH OPEN ald_no_spontaneous_cerebral_animal_model

Attached to

pathophysiology#Inflammatory cerebral demyelination pathophysiology#Microglial and macrophage activation has_subtypes#Childhood cerebral adrenoleukodystrophy

Model evidence exists and is informative for the upstream and metabolic arms of this entry: Abcd1-null animals reproduce VLCFA accumulation, mitochondrial reactive oxygen species, oxidative damage, glial death, and axonal damage, which is why they support the oxidative-stress and axonopathy nodes. What no model reproduces spontaneously is the defining lesion of the cerebral phenotype, namely leukocyte invasion of the brain with inflammatory demyelination. A cerebral phenotype can be obtained only by adding a second, artificial immune insult on the Abcd1-knockout background. Translational validity, not absence of evidence, is therefore the open question for every mechanism curated in this entry between microglial activation and demyelination, and a negative result in an Abcd1-null mouse should not be read as disproof of a human mechanism.

Proposed experiments

Human immune-competent model of cerebral ALD conversion

exp_ald_humanized_immune_cerebral_model

Compare Abcd1-null mice reconstituted with a human immune system against ABCD1-null human brain organoids co-cultured with autologous iPSC-derived microglia and T cells, scoring leukocyte entry, oligodendrocyte death mode, and myelin loss. The comparison isolates whether the missing element is a species difference in the immune compartment or the absence of a human-specific glial or barrier context.

Show evidence (3 references)

PMID:34716609 SUPPORT Model Organism

"Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage."

Establishes what the models do capture, which is the basis for treating them as informative for the metabolic and oxidative nodes of this entry.

PMID:34716609 SUPPORT Model Organism

"cerebral invasion of leukocytes and demyelination were not observed in any animal model for X-ALD, reflecting upon pathological processes that are yet to be discovered"

States the mismatch directly: the cerebral lesion that defines the childhood cerebral subtype has no spontaneous model counterpart.

PMID:39467011 SUPPORT Model Organism

"We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models."

The cerebral phenotype had to be induced by adding demyelinating and autoimmune insults to the ABCD1 defect, which shows the gap is a missing second hit rather than a missing readout.

By what molecular route does ABCD1 loss destroy the adrenal cortex, and why does correcting the hematopoietic compartment not rescue it?

KNOWLEDGE GAP OPEN ald_adrenal_pathogenesis_mechanism

Attached to

pathophysiology#Adrenocortical dysfunction treatments#Hematopoietic stem cell transplantation

Adrenal insufficiency is one of the most common manifestations of ALD, yet the step between VLCFA accumulation and adrenocortical failure is the least characterized part of this entry's pathograph, which currently draws a single direct edge from VLCFA accumulation to adrenocortical dysfunction with no intermediate. The clinical record shows the adrenal arm behaves differently from the cerebral arm: no reversal of established adrenal insufficiency has been reported after transplant or gene therapy, and treated patients continue lifelong glucocorticoid replacement. Whether that reflects a genuinely cell-autonomous pathway, or only irreversible cortical damage already present at treatment, is unresolved. One testable mechanism has emerged: lysosomal cholesterol trapping impairing delivery of substrate for steroidogenesis, with 2-hydroxypropyl-beta-cyclodextrin raising adrenocortical hormone levels in Abcd1-knockout mice. It rests on a single study whose cellular arm used gene knockdown rather than patient material and whose central claim is about peroxisomal disorders generally, so it is recorded here as a lead rather than as a pathograph node.

Proposed experiments

Adrenocortical cholesterol-trafficking test of the lysosomal trapping model

exp_ald_adrenal_cholesterol_trafficking

Differentiate ABCD1-null and isogenic corrected iPSC into adrenocortical organoids, measure lysosomal cholesterol load, mitochondrial cholesterol delivery, and ACTH-stimulated cortisol output, then test whether cyclodextrin restores steroidogenesis. Pair with single-cell transcriptomics of post-mortem ALD adrenal cortex to check that the organoid signature is present in patients.

Show evidence (3 references)

PMID:38034003 SUPPORT Other

"The pathogenesis of X-ALD related PAI is still unclear"

A dedicated review of adrenal involvement in ALD states the mechanistic gap directly rather than leaving it to be inferred.

PMID:38034003 SUPPORT Other

"there is no evidence so far that HCT can change the course of PAI in ALD patients"

Documents that the treatment which halts the cerebral arm leaves the adrenal arm untouched. Note the source frames this as absence of evidence plus absence of reported reversals, not as a demonstrated mechanistic dissociation.

PMID:36971991 SUPPORT Model Organism

"In Abcd1 knockout mice, HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex."

The first pharmacological rescue of adrenal function in an ALD model, and the only currently testable mechanistic proposal for the adrenal arm. Single study, mouse and knockdown-cell evidence only.

Is ferroptosis a distinct mode of cell death in cerebral ALD lesions, or are the iron and lipid-peroxidation findings a downstream marker of demyelination already under way?

EMERGING HYPOTHESIS OPEN ald_ferroptosis_emerging

Attached to

pathophysiology#Inflammatory cerebral demyelination pathophysiology#Oxidative stress

Iron accumulation, myelin peroxidation, and raised ACSL4 have been reported in perilesional white matter, which would place an iron-dependent death pathway alongside the innate and adaptive immune arms already curated here. The finding rests on one study with no intervention arm and no replication, and the authors themselves phrase the conclusion as implicating rather than demonstrating ferroptosis, so it is recorded as an emerging hypothesis rather than as a pathophysiology node. Directionality is the specific problem: perilesional tissue sits at the advancing edge of an active lesion, so the markers are equally consistent with ferroptosis driving lesion expansion and with its being a consequence of ongoing myelin breakdown.

Proposed experiments

Ferroptosis inhibition in the two-hit cerebral ALD mouse model

exp_ald_ferroptosis_inhibitor_two_hit

Treat Abcd1-knockout mice carrying the cuprizone plus experimental autoimmune encephalomyelitis cerebral phenotype with ferrostatin-1 or liproxstatin-1 against vehicle, reading out lesion volume, quantitative susceptibility mapping for iron, and ACSL4 and GPX4 immunohistochemistry. Reduced demyelination under inhibition would establish direction; no effect would place the iron findings downstream.

Show evidence (1 reference)

PMID:41732993 SUPPORT Human Clinical

"In perilesional white matter, increases in myelin peroxidation and Acyl-CoA synthetase long-chain family member 4 are observed."

Reports the imaging and tissue findings behind the ferroptosis proposal. A single study, framed by its authors as implicating rather than establishing the pathway.

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Pathophysiology

10

ABCD1-mediated peroxisomal fatty acid transport defect

Pathogenic ABCD1 variants impair the peroxisomal transporter required to move very long-chain fatty acids into peroxisomes for degradation.

ABCD1 hgnc:61

fatty acid transport GO:0015908 ↓ DECREASED fatty acid beta-oxidation GO:0006635 ↓ DECREASED very long-chain fatty acid metabolic process GO:0000038 ↓ DECREASED

ABC-type fatty-acyl-CoA transporter activity GO:0015607 ↓ DECREASED

peroxisome GO:0005777

Downstream

Very long-chain fatty acid accumulation Impaired peroxisomal transport and beta-oxidation cause VLCFA buildup in blood and tissues.

Show evidence (4 references)

PMID:32101828 SUPPORT Human Clinical

"Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene."

This directly supports ABCD1 as the causal gene for ALD.

PMID:26427835 SUPPORT Human Clinical

"The disease results from pathogenic mutations in the peroxisomal transporter ABCD1 gene"

This supports the peroxisomal transporter defect as the proximal metabolic lesion in ALD.

PMID:36810450 SUPPORT In Vitro

"Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs)."

Cryo-EM structures with a bound C26:0-CoA establish at the molecular level that ALDP recognizes the CoA ester of a very long-chain fatty acid as its transport substrate, which is the step lost in ALD.

+ 1 more reference

Very long-chain fatty acid accumulation

Pathologic elevation of VLCFAs in plasma and tissues, especially affecting brain, spinal cord, and adrenal tissue. Two routes contribute rather than one: loss of ALDP blocks peroxisomal degradation, and it also permits further chain elongation by ELOVL1, so reduced catabolism is compounded by increased synthesis. Toxicity tracks saturation status rather than chain length alone, with saturated species driving ER stress where monounsaturated species do not.

Downstream

Oxidative stress VLCFA excess promotes redox imbalance and oxidative injury that seeds the cerebral inflammatory cascade.

Inflammatory cerebral demyelination VLCFA-mediated tissue injury contributes to the inflammatory cerebral phenotype.

Adrenomyeloneuropathy spinal cord axonopathy VLCFA-mediated injury can also produce the adult spinal-cord and peripheral-nerve-predominant adrenomyeloneuropathy phenotype.

Adrenocortical dysfunction VLCFA accumulation also injures adrenal tissue and contributes to primary adrenal insufficiency.

Gonadal dysfunction VLCFA accumulation can also impair gonadal endocrine function.

Show evidence (4 references)

PMID:32101828 SUPPORT Human Clinical

"Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state."

This directly supports VLCFA accumulation as a biochemical hallmark.

PMID:26427835 SUPPORT Human Clinical

"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."

This links VLCFA accumulation to the major tissue-level manifestations of ALD.

PMID:22483867 SUPPORT Other

"ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues."

Establishes the second arm of the accumulation mechanism: ALDP loss does not only block degradation, it also permits ELOVL1 to elongate the substrate further, so synthesis rises as catabolism falls.

+ 1 more reference

Oxidative stress

Oxidative stress contributes to cellular injury in X-ALD and amplifies the inflammatory cascade that drives the childhood cerebral phenotype.

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

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

Adrenomyeloneuropathy spinal cord 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 CL:0000127

inflammatory response GO:0006954 ↑ 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 GO:0030198 ↕ 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 CL:0000129 macrophage CL:0000235

microglial cell activation GO:0001774 ↑ INCREASED macrophage activation GO:0042116 ↑ INCREASED

Downstream

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

Show evidence (3 references)

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.

PMID:36528616 SUPPORT In Vitro

"VLCFAs provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix-degrading enzymes and chemokine release"

Identifies the receptor route by which accumulated VLCFA primes macrophages, and the same study reports that externally applied VLCFAs do not activate toll-like receptors, so the effect is CD36-specific rather than generic lipid-driven inflammation.

PMID:27779191 SUPPORT Model Organism

"stereotaxic injection of 25-HC into the corpus callosum of mouse brains induces microglial recruitment, interleukin-1β production, and oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner"

Places an NLRP3 inflammasome arm downstream of a sterol metabolite rather than of VLCFA directly, and shows the arm is sufficient on its own to recruit microglia and kill oligodendrocytes in vivo.

Inflammatory cerebral demyelination

Childhood cerebral ALD is marked by rapidly progressive inflammatory white matter demyelination.

oligodendrocyte CL:0000128 microglial cell CL:0000129 CD8 cytotoxic T lymphocyte CL:0000794

inflammatory response GO:0006954 ↑ INCREASED axon ensheathment GO:0008366 ↓ DECREASED

cerebral hemisphere white matter UBERON:0002437

Downstream

CNS demyelination Inflammatory white-matter injury is expressed clinically as CNS demyelination.

Cerebral White Matter Lesions Active cerebral ALD produces symmetric, expanding white matter lesions on brain MRI.

CSF Chitotriosidase Activity Activated monocyte/macrophage neuroinflammation is reported by increased CSF chitotriosidase activity.

Show evidence (2 references)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports inflammatory cerebral demyelination as a major downstream mechanism.

PMID:11589421 SUPPORT Human Clinical

"cytolysis of oligodendrocytes, rather than apoptosis, appears to be the major mode of oligodendrocytic death"

Staged autopsy lesions show CD8 cytotoxic T cells already present in morphologically unaffected white matter and killing oligodendrocytes by cytolysis, adding an adaptive-immune arm to the innate cascade. The same study finds CD1 molecules present and proposes lipid antigen presentation, but that link remains untested.

Adrenomyeloneuropathy spinal cord axonopathy

The adult AMN branch of ALD preferentially affects spinal cord tracts and peripheral/autonomic pathways, producing progressive spastic paraparesis with bladder and bowel dysfunction.

Downstream

Progressive Spastic Paraplegia (AMN) AMN spinal cord tract disease manifests clinically as progressive spastic paraplegia.

Bladder and Bowel Dysfunction (AMN) AMN spinal cord and autonomic pathway involvement produces bladder and bowel dysfunction.

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

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

GeneReviews supports AMN as a progressive adult neurologic phenotype involving spasticity and bladder/bowel dysfunction.

Adrenocortical dysfunction

ALD frequently involves primary adrenal insufficiency due to adrenal cortex dysfunction.

steroid hormone secretion GO:0035929 ↓ DECREASED

adrenal cortex UBERON:0001235

Downstream

Adrenal insufficiency Adrenocortical dysfunction is expressed clinically as adrenal insufficiency.

Cortisol Loss of adrenal cortex steroid hormone secretion is measured as decreased serum cortisol.

ACTH Primary adrenal insufficiency is accompanied by compensatory elevation of plasma ACTH.

Hyperpigmentation of the Skin Primary adrenal insufficiency in ALD can present with increased skin pigmentation.

Weight Loss Addison-form ALD can present with weight loss before neurologic disease is apparent.

Anorexia Addison-form ALD can present with anorexia as part of adrenal insufficiency.

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports adrenal insufficiency as a major tissue-level consequence of ALD.

Gonadal dysfunction

VLCFA-mediated endocrine tissue injury can also impair gonadal function in some affected individuals.

Downstream

Hypogonadism Gonadal dysfunction is expressed clinically as hypogonadism.

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports gonadal dysfunction as an additional endocrine consequence of VLCFA accumulation in ALD.

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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

15

Digestive 1

Anorexia HP:0002039

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"anorexia, weight loss, and skin pigmentation from 18 years of age."

This directly supports anorexia in an Addison-form ALD presentation.

Endocrine 2

Adrenal insufficiency HP:0000846

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports adrenal insufficiency as a core phenotype.

Hypogonadism HP:0000135

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports hypogonadism as part of the recognized endocrine phenotype of ALD.

Eye 1

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.

Integument 1

Hyperpigmentation of the Skin HP:0000953

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"anorexia, weight loss, and skin pigmentation from 18 years of age."

This supports skin pigmentation as a clinical manifestation in Addison-form ALD.

Musculoskeletal 1

Progressive Spastic Paraplegia (AMN) HP:0007020

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

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

GeneReviews documents adrenomyeloneuropathy as the dominant adult neurologic phenotype, characterized by progressive leg weakness, spasticity, and gait disturbance.

Nervous System 7

CNS demyelination HP:0007305

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"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."

This directly supports CNS demyelination as a defining neurologic phenotype.

Cerebral White Matter Lesions Abnormal cerebral white matter morphology HP:0002500

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"Radiographic changes generally precede clinical neurologic disease by several years in childhood cALD and are characterized by symmetric, expanding white matter lesions."

This directly supports cerebral white matter lesions as a radiographic phenotype in cerebral ALD.

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 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 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 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.

Constitutional 1

Bladder and Bowel Dysfunction (AMN) Urinary incontinence HP:0000020

Show evidence (1 reference)

PMID:20301491 SUPPORT Other

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

GeneReviews documents bladder/bowel dysfunction in adult AMN as part of the progressive spinal-cord and autonomic phenotype.

Growth 1

Weight Loss HP:0001824

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old."

This directly supports weight loss in the described ALD Addison-form case.

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Genetic Associations

1

ABCD1 (X-linked causal pathogenic variant)

Gene: ABCD1 hgnc:61 gene page

Show evidence (2 references)

PMID:32101828 SUPPORT Human Clinical

"Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene."

This directly supports ABCD1 as the disease-causing gene.

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

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

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Medical Actions

3

Lentiviral gene therapy (elivaldogene autotemcel / eli-cel)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Autologous CD34+ hematopoietic stem cells transduced with a Lenti-D lentiviral vector carrying ABCD1 cDNA. FDA-approved for early-stage cerebral ALD. In the phase 2-3 ALD-102 / LTF-304 trials with up to 6 years of follow-up, most boys with early cerebral ALD remained free of major functional disabilities; one case of treatment-related myelodysplastic syndrome was reported, identifying insertional oncogenesis as an ongoing risk.

Mechanism Target:

MODULATES Inflammatory cerebral demyelination — Restoring ABCD1 in microglia / hematopoietic progeny reduces VLCFA and halts the cerebral neuroinflammatory cascade.

Show evidence (1 reference)

PMID:39383459 SUPPORT Human Clinical

"At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%."

The ALD-102 phase 2-3 trial validated lentiviral ABCD1 gene therapy as halting cerebral disease progression in early-stage cALD, with 94% overall survival and 100% major-functional-disability-free at 24 months.

Hematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Early hematopoietic stem cell transplantation is the key disease-modifying intervention for cerebral ALD.

Mechanism Target:

MODULATES Inflammatory cerebral demyelination — HSCT is used to arrest cerebral disease progression and may act in part by reducing neuroinflammation.

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"it may, in part, exert its desired effect (arresting further myelin loss) by quelling neuroinflammation."

This supports HSCT as a mechanism-targeted intervention for inflammatory cerebral ALD.

Target Phenotypes: CNS demyelination HP:0007305 Cerebral white matter lesions HP:0002500

Show evidence (1 reference)

PMID:30237433 SUPPORT Human Clinical

"In the cerebral type of ALD, hematopoietic stem cell transplantation is the only treatment in the early stage, and thus prompt diagnosis will improve the prognosis of affected patients."

This directly supports early HSCT as the only disease-modifying therapy for cerebral ALD in the cited review.

Glucocorticoid replacement therapy

Action: Pharmacotherapy NCIT:C15986

Agent: glucocorticoid CHEBI:24261

Glucocorticoid replacement treats the cortisol-deficient adrenal insufficiency presentation of ALD.

Mechanism Target:

BYPASSES Adrenocortical dysfunction — Replacement therapy bypasses impaired adrenal cortisol production by supplying glucocorticoid activity.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"glucocorticoid replacement therapy was initiated."

This supports glucocorticoid replacement as treatment for adrenal insufficiency in ALD.

Target Phenotypes: Adrenal insufficiency HP:0000846

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"glucocorticoid replacement therapy was initiated."

This directly supports glucocorticoid replacement therapy for Addison-form ALD.

🔬

Biochemical Markers

6

Plasma neurofilament light chain (NfL) (INCREASED)

Context: Plasma NfL is a validated prognostic biomarker for cerebral ALD onset and treatment response, with a cut-off of 8.33 pg/mL discriminating cALD with 96% accuracy in an independent validation cohort. A separate retrospective cohort of 14 children treated with HSCT or gene therapy found pre-treatment NfL stratified outcome, with values at or below 113 pg/mL tracking stabilization and values above 243 pg/mL tracking major progression regardless of baseline Loes score; those thresholds are provisional given the cohort size.

Pathograph Readouts

Readout Of Inflammatory cerebral demyelination Positive Prognostic

Elevated plasma NfL reports cerebral axonal injury and predicts cALD onset, supporting early intervention decisions.

Show evidence (2 references)

PMID:37683329 SUPPORT Human Clinical

"A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96%"

Plasma NfL is validated as a high-accuracy biomarker for cerebral ALD onset across multiple independent cohorts.

PMID:41862589 SUPPORT Human Clinical

"Pre-treatment NfL ≤ 113 pg/ml, but not GFAP, correlate with CALD stabilization or, for Loes >9, only minor progression."

Extends the readout from detecting cerebral disease onset to stratifying its outcome after cellular therapy, and shows the stratification is specific to NfL rather than to axonal and glial damage markers generally. The cohort is 14 children, so the thresholds are provisional.

Very-long-chain fatty acids (INCREASED)

Context: Elevated VLCFA levels in plasma are a biochemical hallmark of ALD.

Pathograph Readouts

Readout Of Very long-chain fatty acid accumulation Positive Diagnostic

Elevated plasma VLCFA levels report the biochemical accumulation caused by ABCD1-related peroxisomal transport failure.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state."

This supports elevated VLCFA as a diagnostic readout of ABCD1-related ALD.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state."

This directly supports elevated VLCFA levels as a biochemical hallmark of ALD.

Cortisol (DECREASED)

Context: Low serum cortisol reflects impaired adrenal steroid hormone secretion in Addison-form ALD.

Pathograph Readouts

Readout Of Adrenocortical dysfunction Negative Diagnostic

Low cortisol reports adrenal cortex failure in ALD-related primary adrenal insufficiency.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Endocrinological examination showed low serum cortisol"

This supports low cortisol as a biochemical readout of ALD adrenal involvement.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Endocrinological examination showed low serum cortisol"

This directly supports decreased cortisol in the Addison-form ALD case.

ACTH (INCREASED)

Context: High plasma ACTH reflects primary adrenal insufficiency with adrenal cortex failure.

Pathograph Readouts

Readout Of Adrenocortical dysfunction Positive Diagnostic

Elevated ACTH supports a primary adrenal insufficiency pattern downstream of adrenal cortex dysfunction.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"with high plasma ACTH"

This supports elevated ACTH as a biochemical readout of primary adrenal insufficiency in ALD.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"with high plasma ACTH"

This directly supports increased ACTH in the Addison-form ALD case.

CSF Chitotriosidase Activity (INCREASED)

Context: Increased CSF chitotriosidase activity reports activated monocyte/macrophage inflammation in cerebral ALD and correlates with MRI gadolinium intensity.

Pathograph Readouts

Readout Of Inflammatory cerebral demyelination Positive Prognostic

Higher CSF chitotriosidase activity reports active neuroinflammation in cerebral ALD.

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"CSF chitotriosidase levels, a known inflammatory marker correlating with outcomes following transplantation."

This supports CSF chitotriosidase as a biomarker readout of cerebral ALD neuroinflammation.

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"the score positively correlated with average concomitant CSF chitotriosidase activity"

This supports increased CSF chitotriosidase activity as a measurable inflammatory biomarker in cerebral ALD.

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 Inflammatory cerebral demyelination Positive Monitoring

CSF matrix metalloproteinase elevation reports blood-brain-barrier 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 cerebral 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.

🔬

Diagnosis

4

Plasma very-long-chain fatty acid measurement

Plasma VLCFA testing is a first-line biochemical diagnostic assay for adrenoleukodystrophy.

clinical assessment NCIT:C124351

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state."

This directly supports plasma VLCFA measurement as a core diagnostic assay in ALD.

Molecular genetic testing

Genetic confirmation of an ABCD1 variant establishes the molecular diagnosis.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state."

This supports molecular confirmation of ALD by identifying a pathogenic ABCD1 variant.

Brain MRI

MRI is used to detect cerebral white matter lesions and inflammatory disease progression in cerebral ALD.

magnetic resonance imaging procedure NCIT:C16809

Show evidence (1 reference)

PMID:26427835 SUPPORT Human Clinical

"Radiographic changes generally precede clinical neurologic disease by several years in childhood cALD and are characterized by symmetric, expanding white matter lesions."

This directly supports MRI as a core diagnostic and surveillance tool in cerebral ALD.

Newborn screening for elevated C26:0-lysophosphatidylcholine

C26:0-lysophosphatidylcholine (C26:0-LPC) is measured on the dried blood spot, by flow-injection or liquid-chromatography tandem mass spectrometry; an elevated value is the screening signal for X-ALD and is followed by a repeat or second-tier measurement on the same spot and then ABCD1 sequencing. The analyte is not specific to X-ALD: Zellweger spectrum disorders and other peroxisomal defects also raise it, and in a boys-only programme an X-chromosome count is used as a second tier to avoid identifying heterozygous girls.

newborn screening NCIT:C81178

C26:0-lysophosphatidylcholine (C26:0-LPC), DBS LOINC:79321-6

Reference Ranges

Lysophosphatidylcholine(26:0) [Moles/volume] in DBS (newborn screening, Illinois (USA) programme, initial screening of approximately 276,000 newborns (LC-MS/MS))

Screen negative (< 0.18 umol/L) Borderline, second sample requested (0.18–0.28 umol/L) Screen positive (≥ 0.28 umol/L)

Borderline, second sample requested: Reported only when the initial and repeat analyses both fall here; a second dried blood spot is analysed, and most are normal on that sample.

Screen positive: Referred for confirmatory plasma very-long-chain fatty acid analysis and ABCD1 sequencing; Zellweger spectrum disorders and other peroxisomal conditions also screen positive on this analyte.

The programme states both rules with inclusive lower bounds, "≥ 0.28 µmol/L" for screen positive and "≥0.18 and <0.28 µmol/L" for borderline, which the half-open band convention reproduces exactly: 0.18 is the first borderline value and 0.28 the first positive value. The direction is high: the abnormal tiers are the upper bands. A borderline result is reported only if the initial and repeat analyses both fall in that interval, and is resolved on a second sample; the programme found five of its cases among borderline screens, so the borderline band is not a negative tier.

Show evidence (3 references)

PMID:35076462 SUPPORT Human Clinical

"Results ≥ 0.28 µmol/L were considered screen positive."

States the Illinois programme's dried-blood-spot C26:0-LPC screen-positive threshold.

PMID:35076462 SUPPORT Human Clinical

"Results were reported as borderline if initial and repeat analyses were ≥0.18 and <0.28 µmol/L."

States the borderline interval and that it applies to the initial and repeat analyses together.

PMID:35076462 SUPPORT Human Clinical

"Five X-ALD cases were identified from borderline screens."

Shows that the borderline band yields confirmed cases, so it is an abnormal tier rather than a negative one.

The measurement binds the method-less molar quantitative DBS code; the specimen is intrinsic to a newborn screen, so the DBS code is the test's identity here rather than a method-specific variant, and the LC-MS/MS and mass-concentration variants of the same analyte are not bound. The Illinois figures are recorded as that programme's values for its initial screening period, not as properties of the analyte; the Minnesota programme's observation that every pathogenic or likely pathogenic variant in its first five years had an initial C26:0-LPC over 0.3 μmol/L is a description of its cases, not a cut-off, and is quoted as evidence rather than carried as a band. The pre-existing diagnosis rows on this entry use other NCIT terms because they are confirmatory or surveillance tests, not screens.

Show evidence (2 references)

PMID:35076462 SUPPORT Human Clinical

"The lipid C26:0 lysophosphatidylcholine (C26:0-LPC) was measured in dried blood spots (DBS) using liquid chromatography with tandem mass spectrometry."

Supports the dried-blood-spot C26:0-LPC measurement as the newborn-screening test an operating programme runs for X-ALD.

PMID:39803877 SUPPORT Human Clinical

"All the pathogenic/likely pathogenic variants detected during the first 5 years had initial C26:0 lysophosphatidylcholine (C26:0 lysoPC) values over 0.3 μmol/L at the time of newborn screening."

Documents a second programme's screening C26:0-LPC values in confirmed cases, quoted as a description of cases rather than as a threshold.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from adrenoleukodystrophy:

Addison disease MONDO:0015128

Overlapping Features Isolated primary adrenal insufficiency can be an initial presentation in adult men before neurologic disease makes ALD apparent.

Show evidence (1 reference)

PMID:32101828 SUPPORT Human Clinical

"Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children."

This directly supports idiopathic primary adrenal insufficiency as an important differential context in which ALD should be considered.

Metachromatic leukodystrophy MONDO:0018868

Overlapping Features Other inherited leukodystrophies can overlap radiographically and clinically with the cerebral phenotype of ALD.

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.

📊

Related Datasets

2

Metabolite-phenotype link in X-linked Adrenoleukodystrophy (part II) metabolomics_workbench:ST000742

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("adrenoleukodystrophy"). Retrieved 2026-08-02.

Metabolite-phenotype link in X-linked Adrenoleukodystrophy (fibroblast cell culture) metabolomics_workbench:ST000741

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("adrenoleukodystrophy"). Retrieved 2026-08-02.

🔬

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: adrenoleukodystrophy
creation_date: '2026-04-14T12:05:00Z'
category: Mendelian
description: >-
  Adrenoleukodystrophy is an X-linked peroxisomal disorder caused by pathogenic
  variants in ABCD1, leading to defective degradation of very long-chain fatty
  acids and their accumulation in the nervous system and adrenal cortex. Major
  disease consequences include cerebral demyelination and primary adrenal
  insufficiency.
disease_term:
  preferred_term: adrenoleukodystrophy
  term:
    id: MONDO:0018544
    label: adrenoleukodystrophy
synonyms:
- X-linked adrenoleukodystrophy
- X-ALD
parents:
- hereditary disease
- leukodystrophy
has_subtypes:
- name: Childhood cerebral adrenoleukodystrophy
  subtype_term:
    preferred_term: X-linked cerebral adrenoleukodystrophy
    term:
      id: MONDO:0010247
      label: X-linked cerebral adrenoleukodystrophy
  description: >-
    The inflammatory cerebral form marked by rapidly progressive white-matter
    demyelination and the main subtype considered for early HSCT. Anchored to
    MONDO:0010247, the cerebral child class of the ABCD1 umbrella
    (MONDO:0018544); this subtype carries the cerebral-ALD mechanism that was
    formerly duplicated in a standalone X-linked cerebral ALD entry, which was
    removed in favor of this single ABCD1 pathograph (#4179).
- name: Adrenomyeloneuropathy
  subtype_term:
    preferred_term: adrenomyeloneuropathy
    term:
      id: MONDO:0015339
      label: adrenomyeloneuropathy
  description: >-
    The adult spinal cord and peripheral nerve-predominant form of
    adrenoleukodystrophy.
- name: Addison-only adrenoleukodystrophy
  description: >-
    A presentation with primary adrenal insufficiency before overt
    neurologic disease. No dedicated MONDO leaf class exists for the
    Addison-only ALD form, so no subtype_term is asserted here (the
    autoimmune-Addison class MONDO:0100480 is a distinct disease and must
    not be used).
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Classic adrenoleukodystrophy is inherited as an X-linked recessive
    disorder due to pathogenic ABCD1 variants.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_abcd1_vlcfa_demyelination_adrenal_model
  hypothesis_label: Canonical ABCD1 / VLCFA Accumulation / Demyelination & Adrenal Insufficiency Model
  status: CANONICAL
  description: >-
    X-linked adrenoleukodystrophy (X-ALD) is caused by loss-of-function variants in ABCD1 on Xq28
    encoding the peroxisomal membrane transporter ALDP, which imports very-long-chain fatty acid (VLCFA)
    CoA-esters into the peroxisome for β-oxidation. Loss of ABCD1 function disables peroxisomal
    β-oxidation of saturated VLCFAs (C24:0, C26:0) and produces their pathological accumulation in
    plasma, adrenal cortex, Leydig cells, oligodendrocytes, and CNS myelin. VLCFA accumulation drives
    mitochondrial dysfunction, oxidative stress, microglial activation, and a neuroinflammatory cerebral
    demyelination program, alongside adrenocortical apoptosis producing primary adrenal insufficiency.
    Hematopoietic stem-cell transplantation and lentiviral gene therapy (elivaldogene autotemcel) halt
    cerebral disease progression in early-stage childhood cerebral ALD, corroborating the ABCD1-loss /
    VLCFA-accumulation / neuroinflammatory-demyelination axis as the canonical pathogenic mechanism.
  notes: >-
    Retained as CANONICAL with PARTIALLY SUPPORTED
    qualification (upstream definitive, downstream mechanistically
    incomplete). The 2026 openscientist hypothesis-search report
    (kb/hypotheses/adrenoleukodystrophy/canonical_abcd1_vlcfa_demyelination_adrenal_model)
    confirms 18 findings from 120 papers. Upstream biochemistry is
    definitively established: cryo-EM ABCD1 structure, VLCFA-CoA
    substrate recognition, impaired peroxisomal β-oxidation, and
    ELOVL1-amplified VLCFA accumulation. Lentiviral gene therapy
    (eli-cel/elivaldogene autotemcel; PMID:39383459) and allogeneic
    HSCT provide therapeutic proof-of-concept by halting cerebral
    disease via hematopoietic ABCD1 restoration. Three critical
    downstream refinements limit the model's explanatory power:
    (1) VLCFA accumulation is necessary but not sufficient for
    cerebral inflammatory demyelination — all patients accumulate
    VLCFA but only 35–40% of males develop cerebral ALD, with no
    genotype-phenotype correlation, indicating unknown modifier
    genes and environmental/stochastic factors determine
    phenotypic conversion; (2) no animal model spontaneously
    develops cerebral demyelination despite VLCFA accumulation,
    indicating VLCFA alone cannot drive the inflammatory cerebral
    phenotype; (3) adrenal insufficiency operates through a
    pathway DISTINCT from the neuroinflammatory cascade — HSCT/
    gene therapy fail to correct adrenal dysfunction; first
    therapeutic adrenal rescue achieved through 2-hydroxypropyl-β-
    cyclodextrin (HPCD), suggesting lysosomal cholesterol trapping
    rather than VLCFA toxicity drives adrenocortical apoptosis.
    Six downstream mechanisms converge on tissue damage:
    mitochondrial dysfunction / oxidative stress, NLRP3
    inflammasome via 25-hydroxycholesterol, CD1-mediated lipid
    antigen presentation to CD8 T cells, macrophage CD36/JNK
    priming, ER-stress/UPR activation, and emerging ferroptosis.
    Only saturated VLCFAs are specifically toxic. Plasma
    neurofilament light chain (NfL) is validated as a prognostic
    biomarker for cerebral disease onset and treatment response.
  evidence:
  - reference: PMID:32101828
    reference_title: "A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene."
    explanation: >
      Canonical mechanism reference used as the seed for the
      hypothesis-search deep-research run.
  - reference: PMID:25999754
    reference_title: "The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the molecular basis for the heterogeneity of clinical symptoms is still
      largely unresolved, as no correlation between genotype and phenotype
      exists in X-ALD
    explanation: >-
      Substantiates the qualification recorded in this hypothesis's notes that
      the ABCD1 genotype does not determine which phenotype develops, so
      modifier genes and environmental factors must contribute.
  - reference: PMID:34716609
    reference_title: "ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cerebral invasion of leukocytes and demyelination were not observed in
      any animal model for X-ALD, reflecting upon pathological processes that
      are yet to be discovered
    explanation: >-
      Substantiates the qualification recorded in this hypothesis's notes that
      VLCFA accumulation alone does not produce the cerebral inflammatory
      phenotype, since every published model reproduces the biochemistry
      without the cerebral lesion.
pathophysiology:
- name: ABCD1-mediated peroxisomal fatty acid transport defect
  conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
  description: >-
    Pathogenic ABCD1 variants impair the peroxisomal transporter required to
    move very long-chain fatty acids into peroxisomes for degradation.
  genes:
  - preferred_term: ABCD1
    term:
      id: hgnc:61
      label: ABCD1
  molecular_functions:
  - preferred_term: ABC-type fatty-acyl-CoA transporter activity
    term:
      id: GO:0015607
      label: ABC-type fatty-acyl-CoA transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: fatty acid transport
    term:
      id: GO:0015908
      label: fatty acid transport
    modifier: DECREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  - preferred_term: very long-chain fatty acid metabolic process
    term:
      id: GO:0000038
      label: very long-chain fatty acid metabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  chemical_entities:
  - preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
    modifier: INCREASED
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a
      hemizygous mutation of the ABCD1 gene.
    explanation: >-
      This directly supports ABCD1 as the causal gene for ALD.
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease results from pathogenic mutations in the peroxisomal
      transporter ABCD1 gene
    explanation: >-
      This supports the peroxisomal transporter defect as the proximal
      metabolic lesion in ALD.
  - reference: PMID:36810450
    reference_title: Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane
      domains (TMDs) and stimulates the ATPase activity of the
      nucleotide-binding domains (NBDs).
    explanation: >-
      Cryo-EM structures with a bound C26:0-CoA establish at the molecular
      level that ALDP recognizes the CoA ester of a very long-chain fatty acid
      as its transport substrate, which is the step lost in ALD.
  - reference: PMID:21039332
    reference_title: ABC subfamily D proteins and very long chain fatty acid metabolism as novel targets in adrenoleukodystrophy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      most of the mutant ABCD1s with a missense mutation are degraded rapidly
      by proteasomes before or after targeting to peroxisomes
    explanation: >-
      Identifies proteasomal clearance of the mutant protein, rather than a
      catalytically inert transporter, as the usual molecular route to ALDP
      loss for missense variants.
  downstream:
  - target: Very long-chain fatty acid accumulation
    description: >-
      Impaired peroxisomal transport and beta-oxidation cause VLCFA buildup in
      blood and tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        This supports elevated VLCFAs as the central biochemical mediator of ALD
        tissue manifestations.
- name: Very long-chain fatty acid accumulation
  conforms_to: "peroxisomal_metabolic_failure#Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency"
  description: >-
    Pathologic elevation of VLCFAs in plasma and tissues, especially affecting
    brain, spinal cord, and adrenal tissue. Two routes contribute rather than
    one: loss of ALDP blocks peroxisomal degradation, and it also permits
    further chain elongation by ELOVL1, so reduced catabolism is compounded by
    increased synthesis. Toxicity tracks saturation status rather than chain
    length alone, with saturated species driving ER stress where
    monounsaturated species do not.
  chemical_entities:
  - preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
    modifier: INCREASED
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1
      mutation, p.Gly116Arg, was identified in hemizygous state.
    explanation: >-
      This directly supports VLCFA accumulation as a biochemical hallmark.
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This links VLCFA accumulation to the major tissue-level manifestations of
      ALD.
  - reference: PMID:22483867
    reference_title: "X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain
      fatty acids (VLCFA) and facilitates their further chain elongation by
      ELOVL1 resulting in accumulation of VLCFA in plasma and tissues.
    explanation: >-
      Establishes the second arm of the accumulation mechanism: ALDP loss does
      not only block degradation, it also permits ELOVL1 to elongate the
      substrate further, so synthesis rises as catabolism falls.
  - reference: PMID:33690217
    reference_title: Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts,
      whereas monounsaturated VLCFA did not.
    explanation: >-
      Shows that the toxic species is the saturated VLCFA specifically, which
      is why a total VLCFA measurement is a poor predictor of phenotype and why
      SCD1-mediated desaturation is a therapeutic target.
  downstream:
  - target: Oxidative stress
    description: >-
      VLCFA excess promotes redox imbalance and oxidative injury that seeds the
      cerebral inflammatory cascade.
    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 as the
        upstream step of the cerebral cascade.
  - target: Inflammatory cerebral demyelination
    description: >-
      VLCFA-mediated tissue injury contributes to the inflammatory cerebral
      phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mediated by elevated concentrations of very long chain fatty acids, the
        disease may manifest as central nervous system demyelination
      explanation: >-
        This links elevated VLCFAs to the central nervous system demyelination
        phenotype.
  - target: Adrenomyeloneuropathy spinal cord axonopathy
    description: >-
      VLCFA-mediated injury can also produce the adult spinal-cord and
      peripheral-nerve-predominant adrenomyeloneuropathy phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - spinal cord tract injury
    - peripheral nerve involvement
    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 documents AMN as the adult spinal-cord/peripheral-nerve-predominant ALD phenotype.
  - target: Adrenocortical dysfunction
    description: >-
      VLCFA accumulation also injures adrenal tissue and contributes to primary
      adrenal insufficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mediated by elevated concentrations of very long chain fatty acids, the
        disease may manifest as central nervous system demyelination, primary
        hypoadrenalism
      explanation: >-
        This links elevated VLCFAs to primary hypoadrenalism in ALD.
  - target: Gonadal dysfunction
    description: VLCFA accumulation can also impair gonadal endocrine function.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: >-
        This links elevated VLCFAs to primary hypogonadism as an endocrine
        manifestation of ALD.
- name: Oxidative stress
  description: >-
    Oxidative stress contributes to cellular injury in X-ALD and amplifies the
    inflammatory cascade that drives the childhood cerebral phenotype.
  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 spinal cord 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
  conforms_to: "cns_myelin_failure#Microglial Injury and Reactive Gliosis"
  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.
  - reference: PMID:36528616
    reference_title: Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      VLCFAs provoked pro-inflammatory responses through scavenger receptor
      CD36-mediated uptake, cumulating in JNK signalling and expression of
      matrix-degrading enzymes and chemokine release
    explanation: >-
      Identifies the receptor route by which accumulated VLCFA primes
      macrophages, and the same study reports that externally applied VLCFAs do
      not activate toll-like receptors, so the effect is CD36-specific rather
      than generic lipid-driven inflammation.
  - reference: PMID:27779191
    reference_title: 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      stereotaxic injection of 25-HC into the corpus callosum of mouse brains
      induces microglial recruitment, interleukin-1β production, and
      oligodendrocyte cell death in an NLRP3 inflammasome-dependent manner
    explanation: >-
      Places an NLRP3 inflammasome arm downstream of a sterol metabolite rather
      than of VLCFA directly, and shows the arm is sufficient on its own to
      recruit microglia and kill oligodendrocytes in vivo.
  downstream:
  - target: Inflammatory cerebral demyelination
    description: >-
      Innate immune activation propagates active white-matter destruction.
    causal_link_type: DIRECT
- name: Inflammatory cerebral demyelination
  conforms_to: "cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath"
  description: >-
    Childhood cerebral ALD is marked by rapidly progressive inflammatory white
    matter demyelination.
  locations:
  - preferred_term: cerebral hemisphere white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: CD8 cytotoxic T lymphocyte
    term:
      id: CL:0000794
      label: "CD8-positive, alpha-beta cytotoxic T cell"
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: axon ensheathment
    term:
      id: GO:0008366
      label: axon ensheathment
    modifier: DECREASED
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports inflammatory cerebral demyelination as a major
      downstream mechanism.
  - reference: PMID:11589421
    reference_title: "Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cytolysis of oligodendrocytes, rather than apoptosis, appears to be the
      major mode of oligodendrocytic death
    explanation: >-
      Staged autopsy lesions show CD8 cytotoxic T cells already present in
      morphologically unaffected white matter and killing oligodendrocytes by
      cytolysis, adding an adaptive-immune arm to the innate cascade. The same
      study finds CD1 molecules present and proposes lipid antigen
      presentation, but that link remains untested.
  downstream:
  - target: CNS demyelination
    description: Inflammatory white-matter injury is expressed clinically as CNS demyelination.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This devastating phenotype is characterized by rapidly progressive
        central nervous demyelination
      explanation: >-
        This directly supports CNS demyelination as the clinical expression of
        the cerebral inflammatory lesion.
  - target: Cerebral White Matter Lesions
    description: Active cerebral ALD produces symmetric, expanding white matter lesions on brain MRI.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiographic changes generally precede clinical neurologic disease by
        several years in childhood cALD and are characterized by symmetric,
        expanding white matter lesions.
      explanation: >-
        This supports cerebral white matter lesions as an early radiographic
        manifestation of cerebral ALD.
  - target: CSF Chitotriosidase Activity
    description: Activated monocyte/macrophage neuroinflammation is reported by increased CSF chitotriosidase activity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CSF chitotriosidase levels, a known inflammatory marker correlating
        with outcomes following transplantation.
      explanation: >-
        This supports CSF chitotriosidase activity as a biomarker readout of
        inflammatory cerebral ALD.
- name: Adrenomyeloneuropathy spinal cord axonopathy
  description: >-
    The adult AMN branch of ALD preferentially affects spinal cord tracts and
    peripheral/autonomic pathways, producing progressive spastic paraparesis
    with bladder and bowel dysfunction.
  subtypes:
  - Adrenomyeloneuropathy
  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 supports AMN as a progressive adult neurologic phenotype involving spasticity and bladder/bowel dysfunction.
  downstream:
  - target: Progressive Spastic Paraplegia (AMN)
    causal_link_type: DIRECT
    description: AMN spinal cord tract disease manifests clinically as progressive spastic paraplegia.
    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 documents leg weakness, spasticity, and gait disturbance in AMN.
  - target: Bladder and Bowel Dysfunction (AMN)
    causal_link_type: DIRECT
    description: AMN spinal cord and autonomic pathway involvement produces bladder and bowel dysfunction.
    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 documents bladder and bowel dysfunction as part of AMN.
- name: Adrenocortical dysfunction
  description: >-
    ALD frequently involves primary adrenal insufficiency due to adrenal cortex
    dysfunction.
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  biological_processes:
  - preferred_term: steroid hormone secretion
    term:
      id: GO:0035929
      label: steroid hormone secretion
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
    modifier: DECREASED
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports adrenal insufficiency as a major tissue-level
      consequence of ALD.
  downstream:
  - target: Adrenal insufficiency
    description: Adrenocortical dysfunction is expressed clinically as adrenal insufficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mediated by elevated concentrations of very long chain fatty acids, the
        disease may manifest as central nervous system demyelination, primary
        hypoadrenalism
      explanation: >-
        This supports primary hypoadrenalism as the clinical output of adrenal
        cortex dysfunction in ALD.
  - target: Cortisol
    description: Loss of adrenal cortex steroid hormone secretion is measured as decreased serum cortisol.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Endocrinological examination showed low serum cortisol
      explanation: This supports decreased cortisol as a biochemical readout of adrenal insufficiency in ALD.
  - target: ACTH
    description: Primary adrenal insufficiency is accompanied by compensatory elevation of plasma ACTH.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: with high plasma ACTH
      explanation: This supports elevated ACTH as a biochemical readout of primary adrenal insufficiency in ALD.
  - target: Hyperpigmentation of the Skin
    description: Primary adrenal insufficiency in ALD can present with increased skin pigmentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: anorexia, weight loss, and skin pigmentation from 18 years of age.
      explanation: The case report supports skin pigmentation as part of the Addison-form ALD presentation.
  - target: Weight Loss
    description: Addison-form ALD can present with weight loss before neurologic disease is apparent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old.
      explanation: The case report directly supports weight loss in an Addison-form ALD presentation.
  - target: Anorexia
    description: Addison-form ALD can present with anorexia as part of adrenal insufficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: anorexia, weight loss, and skin pigmentation from 18 years of age.
      explanation: The case report directly supports anorexia in an Addison-form ALD presentation.
- name: Gonadal dysfunction
  description: >-
    VLCFA-mediated endocrine tissue injury can also impair gonadal function in
    some affected individuals.
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports gonadal dysfunction as an additional endocrine
      consequence of VLCFA accumulation in ALD.
  downstream:
  - target: Hypogonadism
    description: Gonadal dysfunction is expressed clinically as hypogonadism.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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.
      explanation: This supports hypogonadism as the clinical output of gonadal dysfunction in ALD.
phenotypes:
- name: Progressive Spastic Paraplegia (AMN)
  category: Neurological
  subtype: Adrenomyeloneuropathy
  description: >-
    Progressive spastic paraplegia is the dominant adult neurological
    manifestation in adrenomyeloneuropathy (AMN), reflecting distal
    axonopathy of the corticospinal tracts and posterior columns.
  phenotype_term:
    preferred_term: Progressive spastic paraplegia
    term:
      id: HP:0007020
      label: Progressive spastic paraplegia
  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 documents adrenomyeloneuropathy as the dominant adult
      neurologic phenotype, characterized by progressive leg weakness,
      spasticity, and gait disturbance.
- name: Bladder and Bowel Dysfunction (AMN)
  category: Genitourinary
  subtype: Adrenomyeloneuropathy
  description: >-
    Urinary urgency, incontinence, and bowel dysfunction are recognized
    AMN-associated phenotypes attributable to spinal-cord and autonomic
    involvement.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  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 documents bladder/bowel dysfunction in adult AMN as
      part of the progressive spinal-cord and autonomic phenotype.
- name: Adrenal insufficiency
  category: Endocrine
  diagnostic: true
  description: >-
    Primary adrenal insufficiency is a major endocrine presentation of ALD and
    may precede neurologic disease.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports adrenal insufficiency as a core phenotype.
- name: Hyperpigmentation of the Skin
  category: Endocrine
  description: >-
    Addison-form ALD can present with increased skin pigmentation as part of
    primary adrenal insufficiency.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: anorexia, weight loss, and skin pigmentation from 18 years of age.
    explanation: This supports skin pigmentation as a clinical manifestation in Addison-form ALD.
- name: Weight Loss
  category: Constitutional
  description: >-
    Weight loss can accompany the Addison-only presentation of ALD before
    neurologic signs are detected.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old.
    explanation: This directly supports weight loss in the described ALD Addison-form case.
- name: Anorexia
  category: Gastrointestinal
  description: >-
    Anorexia can be part of the adrenal-insufficiency presentation of ALD.
  phenotype_term:
    preferred_term: Anorexia
    term:
      id: HP:0002039
      label: Anorexia
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: anorexia, weight loss, and skin pigmentation from 18 years of age.
    explanation: This directly supports anorexia in an Addison-form ALD presentation.
- name: CNS demyelination
  category: Neurologic
  diagnostic: true
  description: >-
    Progressive cerebral white matter demyelination is the major neurologic
    lesion in cerebral ALD.
  phenotype_term:
    preferred_term: CNS demyelination
    term:
      id: HP:0007305
      label: CNS demyelination
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports CNS demyelination as a defining neurologic
      phenotype.
- name: Cerebral White Matter Lesions
  category: Neurologic
  diagnostic: true
  description: >-
    Brain MRI can show symmetric, expanding cerebral white matter lesions before
    overt neurologic symptoms in childhood cerebral ALD.
  phenotype_term:
    preferred_term: Cerebral white matter lesions
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic changes generally precede clinical neurologic disease by
      several years in childhood cALD and are characterized by symmetric,
      expanding white matter lesions.
    explanation: >-
      This directly supports cerebral white matter lesions as a radiographic
      phenotype in cerebral ALD.
- name: Hypogonadism
  category: Endocrine
  description: >-
    Primary hypogonadism can occur as part of the broader endocrine phenotype
    of adrenoleukodystrophy.
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      This directly supports hypogonadism as part of the recognized endocrine
      phenotype of ALD.
- name: Leukoencephalopathy
  category: Neurologic
  subtype: Childhood cerebral adrenoleukodystrophy
  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
  subtype: Childhood cerebral adrenoleukodystrophy
  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
  subtype: Childhood cerebral adrenoleukodystrophy
  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
  subtype: Childhood cerebral adrenoleukodystrophy
  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
  subtype: Adrenomyeloneuropathy
  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: Peripheral neuropathy
  category: Neurologic
  subtype: Adrenomyeloneuropathy
  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.
biochemical:
- name: Plasma neurofilament light chain (NfL)
  presence: INCREASED
  context: >-
    Plasma NfL is a validated prognostic biomarker for cerebral ALD onset
    and treatment response, with a cut-off of 8.33 pg/mL discriminating
    cALD with 96% accuracy in an independent validation cohort. A separate
    retrospective cohort of 14 children treated with HSCT or gene therapy
    found pre-treatment NfL stratified outcome, with values at or below
    113 pg/mL tracking stabilization and values above 243 pg/mL tracking
    major progression regardless of baseline Loes score; those thresholds
    are provisional given the cohort size.
  biomarker_term:
    preferred_term: neurofilament light polypeptide
    term:
      id: NCIT:C88043
      label: Neurofilament Light Polypeptide
  readouts:
  - target: Inflammatory cerebral demyelination
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Elevated plasma NfL reports cerebral axonal injury and predicts cALD
      onset, supporting early intervention decisions.
    evidence:
    - reference: PMID:37683329
      reference_title: "Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96%"
      explanation: >-
        Plasma NfL is validated as a high-accuracy biomarker for cerebral
        ALD onset across multiple independent cohorts.
    - reference: PMID:41862589
      reference_title: Pretreatment blood NfL indicates response to cellular therapies in cerebral adrenoleukodystrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pre-treatment NfL ≤ 113 pg/ml, but not GFAP, correlate with CALD
        stabilization or, for Loes >9, only minor progression.
      explanation: >-
        Extends the readout from detecting cerebral disease onset to
        stratifying its outcome after cellular therapy, and shows the
        stratification is specific to NfL rather than to axonal and glial
        damage markers generally. The cohort is 14 children, so the
        thresholds are provisional.
- name: Very-long-chain fatty acids
  presence: INCREASED
  context: Elevated VLCFA levels in plasma are a biochemical hallmark of ALD.
  loinc_term:
    id: LOINC:43677-4
    label: Fatty acid very long chain (C22-C26) panel - Serum or Plasma
  notes: >-
    The marker describes the plasma very-long-chain fatty acid profile, so
    loinc_term binds the serum-or-plasma panel code rather than any single
    species or ratio; the newborn-screening analyte, C26:0-lysophosphatidylcholine
    in the dried blood spot, is a different measurement and sits on the
    newborn-screening diagnosis row.
  biomarker_term:
    preferred_term: very long-chain fatty acid
    term:
      id: CHEBI:27283
      label: very long-chain fatty acid
  readouts:
  - target: Very long-chain fatty acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated plasma VLCFA levels report the biochemical accumulation caused by
      ABCD1-related peroxisomal transport failure.
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1
        mutation, p.Gly116Arg, was identified in hemizygous state.
      explanation: This supports elevated VLCFA as a diagnostic readout of ABCD1-related ALD.
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1
      mutation, p.Gly116Arg, was identified in hemizygous state.
    explanation: This directly supports elevated VLCFA levels as a biochemical hallmark of ALD.
- name: Cortisol
  presence: DECREASED
  context: Low serum cortisol reflects impaired adrenal steroid hormone secretion in Addison-form ALD.
  biomarker_term:
    preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  readouts:
  - target: Adrenocortical dysfunction
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low cortisol reports adrenal cortex failure in ALD-related primary adrenal insufficiency.
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Endocrinological examination showed low serum cortisol
      explanation: This supports low cortisol as a biochemical readout of ALD adrenal involvement.
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Endocrinological examination showed low serum cortisol
    explanation: This directly supports decreased cortisol in the Addison-form ALD case.
- name: ACTH
  presence: INCREASED
  context: High plasma ACTH reflects primary adrenal insufficiency with adrenal cortex failure.
  biomarker_term:
    preferred_term: corticotropin
    term:
      id: CHEBI:3892
      label: corticotropin
  readouts:
  - target: Adrenocortical dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated ACTH supports a primary adrenal insufficiency pattern downstream of adrenal cortex dysfunction.
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: with high plasma ACTH
      explanation: This supports elevated ACTH as a biochemical readout of primary adrenal insufficiency in ALD.
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with high plasma ACTH
    explanation: This directly supports increased ACTH in the Addison-form ALD case.
- name: CSF Chitotriosidase Activity
  presence: INCREASED
  context: >-
    Increased CSF chitotriosidase activity reports activated
    monocyte/macrophage inflammation in cerebral ALD and correlates with MRI
    gadolinium intensity.
  readouts:
  - target: Inflammatory cerebral demyelination
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: Higher CSF chitotriosidase activity reports active neuroinflammation in cerebral ALD.
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CSF chitotriosidase levels, a known inflammatory marker correlating
        with outcomes following transplantation.
      explanation: This supports CSF chitotriosidase as a biomarker readout of cerebral ALD neuroinflammation.
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the score positively correlated with average concomitant CSF
      chitotriosidase activity
    explanation: This supports increased CSF chitotriosidase activity as a measurable inflammatory biomarker in cerebral ALD.
- 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: Inflammatory cerebral demyelination
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      CSF matrix metalloproteinase elevation reports blood-brain-barrier
      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 cerebral 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.
genetic:
- name: ABCD1
  gene_term:
    preferred_term: ABCD1
    term:
      id: hgnc:61
      label: ABCD1
  association: X-linked causal pathogenic variant
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a
      hemizygous mutation of the ABCD1 gene.
    explanation: >-
      This directly supports ABCD1 as the disease-causing gene.
  - reference: CGGV:assertion_815e0f84-b530-4fd2-81a9-02e02bf352ee-2020-12-18T050000.000Z
    reference_title: "ABCD1 / adrenoleukodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ABCD1 | HGNC:61 | adrenoleukodystrophy | MONDO:0018544 | XL | Definitive"
    explanation: ClinGen classifies the ABCD1-adrenoleukodystrophy gene-disease relationship as definitive with X-linked inheritance.
environmental: []
treatments:
- name: Lentiviral gene therapy (elivaldogene autotemcel / eli-cel)
  description: >-
    Autologous CD34+ hematopoietic stem cells transduced with a Lenti-D
    lentiviral vector carrying ABCD1 cDNA. FDA-approved for early-stage
    cerebral ALD. In the phase 2-3 ALD-102 / LTF-304 trials with up to
    6 years of follow-up, most boys with early cerebral ALD remained
    free of major functional disabilities; one case of treatment-related
    myelodysplastic syndrome was reported, identifying insertional
    oncogenesis as an ongoing risk.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:39383459
    reference_title: "Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%."
    explanation: >-
      The ALD-102 phase 2-3 trial validated lentiviral ABCD1 gene therapy
      as halting cerebral disease progression in early-stage cALD, with
      94% overall survival and 100% major-functional-disability-free at
      24 months.
  target_mechanisms:
  - target: Inflammatory cerebral demyelination
    treatment_effect: MODULATES
    description: >-
      Restoring ABCD1 in microglia / hematopoietic progeny reduces VLCFA
      and halts the cerebral neuroinflammatory cascade.
- name: Hematopoietic stem cell transplantation
  description: >-
    Early hematopoietic stem cell transplantation is the key disease-modifying
    intervention for cerebral ALD.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: PMID:30237433
    reference_title: Expanding the concept of peroxisomal diseases and efficient diagnostic system in Japan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the cerebral type of ALD, hematopoietic stem cell transplantation is
      the only treatment in the early stage, and thus prompt diagnosis will
      improve the prognosis of affected patients.
    explanation: >-
      This directly supports early HSCT as the only disease-modifying therapy
      for cerebral ALD in the cited review.
  target_mechanisms:
  - target: Inflammatory cerebral demyelination
    treatment_effect: MODULATES
    description: HSCT is used to arrest cerebral disease progression and may act in part by reducing neuroinflammation.
    evidence:
    - reference: PMID:26427835
      reference_title: >-
        Intensity of MRI Gadolinium Enhancement in Cerebral
        Adrenoleukodystrophy: A Biomarker for Inflammation and Predictor of
        Outcome following Transplantation in Higher Risk Patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        it may, in part, exert its desired effect (arresting further myelin
        loss) by quelling neuroinflammation.
      explanation: This supports HSCT as a mechanism-targeted intervention for inflammatory cerebral ALD.
  target_phenotypes:
  - preferred_term: CNS demyelination
    term:
      id: HP:0007305
      label: CNS demyelination
  - preferred_term: Cerebral white matter lesions
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
- name: Glucocorticoid replacement therapy
  description: >-
    Glucocorticoid replacement treats the cortisol-deficient adrenal
    insufficiency presentation of ALD.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glucocorticoid
      term:
        id: CHEBI:24261
        label: glucocorticoid
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: glucocorticoid replacement therapy was initiated.
    explanation: This directly supports glucocorticoid replacement therapy for Addison-form ALD.
  target_mechanisms:
  - target: Adrenocortical dysfunction
    treatment_effect: BYPASSES
    description: Replacement therapy bypasses impaired adrenal cortisol production by supplying glucocorticoid activity.
    evidence:
    - reference: PMID:32101828
      reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: glucocorticoid replacement therapy was initiated.
      explanation: This supports glucocorticoid replacement as treatment for adrenal insufficiency in ALD.
  target_phenotypes:
  - preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
diagnosis:
- name: Plasma very-long-chain fatty acid measurement
  description: >-
    Plasma VLCFA testing is a first-line biochemical diagnostic assay for
    adrenoleukodystrophy.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1
      mutation, p.Gly116Arg, was identified in hemizygous state.
    explanation: >-
      This directly supports plasma VLCFA measurement as a core diagnostic
      assay in ALD.
- name: Molecular genetic testing
  description: >-
    Genetic confirmation of an ABCD1 variant establishes the molecular
    diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1
      mutation, p.Gly116Arg, was identified in hemizygous state.
    explanation: >-
      This supports molecular confirmation of ALD by identifying a pathogenic
      ABCD1 variant.
- name: Brain MRI
  description: >-
    MRI is used to detect cerebral white matter lesions and inflammatory disease
    progression in cerebral ALD.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:26427835
    reference_title: >-
      Intensity of MRI Gadolinium Enhancement in Cerebral Adrenoleukodystrophy:
      A Biomarker for Inflammation and Predictor of Outcome following
      Transplantation in Higher Risk Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographic changes generally precede clinical neurologic disease by
      several years in childhood cALD and are characterized by symmetric,
      expanding white matter lesions.
    explanation: >-
      This directly supports MRI as a core diagnostic and surveillance tool in
      cerebral ALD.
- name: Newborn screening for elevated C26:0-lysophosphatidylcholine
  description: >-
    C26:0-lysophosphatidylcholine (C26:0-LPC) is measured on the dried blood
    spot, by flow-injection or liquid-chromatography tandem mass spectrometry;
    an elevated value is the screening signal for X-ALD and is followed by a
    repeat or second-tier measurement on the same spot and then ABCD1
    sequencing. The analyte is not specific to X-ALD: Zellweger spectrum
    disorders and other peroxisomal defects also raise it, and in a boys-only
    programme an X-chromosome count is used as a second tier to avoid
    identifying heterozygous girls.
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  measurements:
  - preferred_term: C26:0-lysophosphatidylcholine (C26:0-LPC), DBS
    term:
      id: LOINC:79321-6
      label: Lysophosphatidylcholine(26:0) [Moles/volume] in DBS
  reference_ranges:
  - loinc_term:
      id: LOINC:79321-6
      label: Lysophosphatidylcholine(26:0) [Moles/volume] in DBS
    unit: umol/L
    population: newborn screening, Illinois (USA) programme, initial screening of approximately 276,000 newborns (LC-MS/MS)
    notes: >-
      The programme states both rules with inclusive lower bounds, "≥ 0.28
      µmol/L" for screen positive and "≥0.18 and <0.28 µmol/L" for borderline,
      which the half-open band convention reproduces exactly: 0.18 is the first
      borderline value and 0.28 the first positive value. The direction is
      high: the abnormal tiers are the upper bands. A borderline result is
      reported only if the initial and repeat analyses both fall in that
      interval, and is resolved on a second sample; the programme found five of
      its cases among borderline screens, so the borderline band is not a
      negative tier.
    evidence:
    - reference: PMID:35076462
      reference_title: "Newborn Screening for X-Linked Adrenoleukodystrophy: The Initial Illinois Experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Results ≥ 0.28 µmol/L were considered screen positive."
      explanation: States the Illinois programme's dried-blood-spot C26:0-LPC screen-positive threshold.
    - reference: PMID:35076462
      reference_title: "Newborn Screening for X-Linked Adrenoleukodystrophy: The Initial Illinois Experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Results were reported as borderline if initial and repeat analyses were ≥0.18 and <0.28 µmol/L."
      explanation: States the borderline interval and that it applies to the initial and repeat analyses together.
    - reference: PMID:35076462
      reference_title: "Newborn Screening for X-Linked Adrenoleukodystrophy: The Initial Illinois Experience."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Five X-ALD cases were identified from borderline screens."
      explanation: Shows that the borderline band yields confirmed cases, so it is an abnormal tier rather than a negative one.
    interpretation_bands:
    - name: Screen negative
      upper_bound: 0.18
      unit: umol/L
      abnormal_flag: NORMAL
    - name: Borderline, second sample requested
      lower_bound: 0.18
      upper_bound: 0.28
      unit: umol/L
      abnormal_flag: HIGH
      interpretation: >-
        Reported only when the initial and repeat analyses both fall here; a
        second dried blood spot is analysed, and most are normal on that sample.
    - name: Screen positive
      lower_bound: 0.28
      unit: umol/L
      abnormal_flag: HIGH
      interpretation: >-
        Referred for confirmatory plasma very-long-chain fatty acid analysis
        and ABCD1 sequencing; Zellweger spectrum disorders and other
        peroxisomal conditions also screen positive on this analyte.
  notes: >-
    The measurement binds the method-less molar quantitative DBS code; the
    specimen is intrinsic to a newborn screen, so the DBS code is the test's
    identity here rather than a method-specific variant, and the LC-MS/MS and
    mass-concentration variants of the same analyte are not bound. The
    Illinois figures are recorded as that programme's values for its initial
    screening period, not as properties of the analyte; the Minnesota
    programme's observation that every pathogenic or likely pathogenic variant
    in its first five years had an initial C26:0-LPC over 0.3 μmol/L is a
    description of its cases, not a cut-off, and is quoted as evidence rather
    than carried as a band. The pre-existing diagnosis rows on this entry use
    other NCIT terms because they are confirmatory or surveillance tests, not
    screens.
  evidence:
  - reference: PMID:35076462
    reference_title: "Newborn Screening for X-Linked Adrenoleukodystrophy: The Initial Illinois Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lipid C26:0 lysophosphatidylcholine (C26:0-LPC) was measured in dried blood spots (DBS) using liquid chromatography with tandem mass spectrometry."
    explanation: Supports the dried-blood-spot C26:0-LPC measurement as the newborn-screening test an operating programme runs for X-ALD.
  - reference: PMID:39803877
    reference_title: "Insights From Minnesota on Newborn Screening for Adrenoleukodystrophy: A 5-Year Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the pathogenic/likely pathogenic variants detected during the first 5 years had initial C26:0 lysophosphatidylcholine (C26:0 lysoPC) values over 0.3 μmol/L at the time of newborn screening."
    explanation: Documents a second programme's screening C26:0-LPC values in confirmed cases, quoted as a description of cases rather than as a threshold.
differential_diagnoses:
- name: Addison disease
  description: >-
    Isolated primary adrenal insufficiency can be an initial presentation in
    adult men before neurologic disease makes ALD apparent.
  disease_term:
    preferred_term: primary adrenal insufficiency
    term:
      id: MONDO:0015128
      label: primary adrenal insufficiency
  evidence:
  - reference: PMID:32101828
    reference_title: A 29-year-old patient with adrenoleukodystrophy presenting with Addison's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Evaluating VLCFA levels for ALD diagnosis is important in young adult men
      with idiopathic primary adrenal insufficiency as well as in children.
    explanation: >-
      This directly supports idiopathic primary adrenal insufficiency as an
      important differential context in which ALD should be considered.
- name: Metachromatic leukodystrophy
  description: >-
    Other inherited leukodystrophies can overlap radiographically and
    clinically with the cerebral phenotype of ALD.
  disease_term:
    preferred_term: metachromatic leukodystrophy
    term:
      id: MONDO:0018868
      label: metachromatic leukodystrophy
- 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.
references:
- reference: PMID:20301491
  title: X-Linked Adrenoleukodystrophy.
  tags:
  - GeneReviews
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
    reference_title: "A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)"
    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
    reference_title: "A Randomized, Double-blind, Placebo-controlled, Multinational, Multicenter Study With Open-label Treatment Extension to Assess the Effect of MIN-102 (IMP) on the Progression of Adrenomyeloneuropathy in Male Patients With X-linked Adrenoleukodystrophy"
    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
    reference_title: "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)"
    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.
datasets:
- accession: metabolomics_workbench:ST000742
  title: Metabolite-phenotype link in X-linked Adrenoleukodystrophy (part II)
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("adrenoleukodystrophy"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST000741
  title: Metabolite-phenotype link in X-linked Adrenoleukodystrophy (fibroblast cell culture)
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("adrenoleukodystrophy"). Retrieved 2026-08-02.
discussions:
- discussion_id: ald_cerebral_conversion_trigger
  prompt: >-
    What determines which males carrying an ABCD1 variant convert to the
    cerebral inflammatory phenotype, given that every patient accumulates VLCFA
    and the ABCD1 genotype does not predict the outcome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Very long-chain fatty acid accumulation
  - pathophysiology#Inflammatory cerebral demyelination
  - mechanistic_hypotheses#canonical_abcd1_vlcfa_demyelination_adrenal_model
  rationale: >-
    This is the central unresolved question in X-ALD and the reason the
    canonical model is annotated as necessary but not sufficient downstream.
    The genotype carries no phenotype information, so modifier genes,
    environmental exposure, or stochastic factors must decide conversion, and
    none has been identified: candidate-gene work on the CD1 locus, other ABCD
    paralogues, and methionine metabolism has not replicated, and no
    genome-wide association study has been published. The therapeutic corollary
    is that normalizing plasma VLCFA is not by itself sufficient, as the
    Lorenzo's oil visual-pathway trial showed. Without the trigger, prevention
    is impossible and management stays reactive MRI surveillance. Note that the
    conversion fraction itself is cohort- and age-dependent: reviews commonly
    quote 35 to 40 percent of males while the Danish national cohort reports
    44 percent by age 60, so no single figure should be curated as settled.
  proposed_experiments:
  - experiment_id: exp_ald_modifier_gwas_ewas
    name: Phenotype-stratified ALD modifier GWAS and EWAS
    description: >-
      Assemble newborn-screening-identified and clinically phenotyped males
      across an international consortium, stratify by cerebral ALD versus
      adrenomyeloneuropathy versus asymptomatic status at a fixed age
      threshold, and run genome-wide genotyping with imputation plus
      epigenome-wide methylation on matched samples. A null result at adequate
      power would itself be informative, shifting weight toward stochastic or
      environmental determination.
  evidence:
  - reference: PMID:25999754
    reference_title: "The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Beyond ABCD1, environmental triggers and other genetic factors have been
      suggested as modifiers of the disease course.
    explanation: >-
      A review of the modifier-gene literature concluding that the determinants
      of phenotype remain unidentified despite repeated searches.
  - reference: PMID:8338341
    reference_title: "Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol trioleate and Lorenzo oil."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was no evidence that reduction of VLCFA levels improved or retarded
      visual pathway demyelination
    explanation: >-
      Lowering plasma VLCFA markedly, without arresting demyelination, is
      direct clinical evidence that the VLCFA level is not the proximate
      determinant of neurological progression once disease is established.
  - reference: PMID:41166774
    reference_title: Nationwide Study of the Epidemiology and Clinical Features of X-Linked Adrenoleukodystrophy in Denmark.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 %
      had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency.
    explanation: >-
      A genetically ascertained national cohort quantifies the incomplete and
      divergent penetrance of the three arms, which is the observation the gap
      is about.
- discussion_id: ald_no_spontaneous_cerebral_animal_model
  prompt: >-
    Does any available animal model reproduce the cerebral inflammatory
    demyelination of childhood cerebral ALD without artificial immune
    provocation, and what does the failure to do so say about the missing step?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Inflammatory cerebral demyelination
  - pathophysiology#Microglial and macrophage activation
  - has_subtypes#Childhood cerebral adrenoleukodystrophy
  rationale: >-
    Model evidence exists and is informative for the upstream and metabolic
    arms of this entry: Abcd1-null animals reproduce VLCFA accumulation,
    mitochondrial reactive oxygen species, oxidative damage, glial death, and
    axonal damage, which is why they support the oxidative-stress and
    axonopathy nodes. What no model reproduces spontaneously is the defining
    lesion of the cerebral phenotype, namely leukocyte invasion of the brain
    with inflammatory demyelination. A cerebral phenotype can be obtained only
    by adding a second, artificial immune insult on the Abcd1-knockout
    background. Translational validity, not absence of evidence, is therefore
    the open question for every mechanism curated in this entry between
    microglial activation and demyelination, and a negative result in an
    Abcd1-null mouse should not be read as disproof of a human mechanism.
  proposed_experiments:
  - experiment_id: exp_ald_humanized_immune_cerebral_model
    name: Human immune-competent model of cerebral ALD conversion
    description: >-
      Compare Abcd1-null mice reconstituted with a human immune system against
      ABCD1-null human brain organoids co-cultured with autologous
      iPSC-derived microglia and T cells, scoring leukocyte entry,
      oligodendrocyte death mode, and myelin loss. The comparison isolates
      whether the missing element is a species difference in the immune
      compartment or the absence of a human-specific glial or barrier context.
  evidence:
  - reference: PMID:34716609
    reference_title: "ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Animal models for the disease recapitulate the biochemical signature of
      VLCFA accumulation and demonstrate mitochondrially generated reactive
      oxygen species, oxidative damage, increased glial death, and axonal
      damage.
    explanation: >-
      Establishes what the models do capture, which is the basis for treating
      them as informative for the metabolic and oxidative nodes of this entry.
  - reference: PMID:34716609
    reference_title: "ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cerebral invasion of leukocytes and demyelination were not observed in
      any animal model for X-ALD, reflecting upon pathological processes that
      are yet to be discovered
    explanation: >-
      States the mismatch directly: the cerebral lesion that defines the
      childhood cerebral subtype has no spontaneous model counterpart.
  - reference: PMID:39467011
    reference_title: "A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method
      that combines cuprizone and experimental autoimmune encephalomyelitis
      models.
    explanation: >-
      The cerebral phenotype had to be induced by adding demyelinating and
      autoimmune insults to the ABCD1 defect, which shows the gap is a missing
      second hit rather than a missing readout.
- discussion_id: ald_adrenal_pathogenesis_mechanism
  prompt: >-
    By what molecular route does ABCD1 loss destroy the adrenal cortex, and why
    does correcting the hematopoietic compartment not rescue it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Adrenocortical dysfunction
  - treatments#Hematopoietic stem cell transplantation
  rationale: >-
    Adrenal insufficiency is one of the most common manifestations of ALD, yet
    the step between VLCFA accumulation and adrenocortical failure is the least
    characterized part of this entry's pathograph, which currently draws a
    single direct edge from VLCFA accumulation to adrenocortical dysfunction
    with no intermediate. The clinical record shows the adrenal arm behaves
    differently from the cerebral arm: no reversal of established adrenal
    insufficiency has been reported after transplant or gene therapy, and
    treated patients continue lifelong glucocorticoid replacement. Whether that
    reflects a genuinely cell-autonomous pathway, or only irreversible cortical
    damage already present at treatment, is unresolved. One testable mechanism
    has emerged: lysosomal cholesterol trapping impairing delivery of substrate
    for steroidogenesis, with 2-hydroxypropyl-beta-cyclodextrin raising
    adrenocortical hormone levels in Abcd1-knockout mice. It rests on a single
    study whose cellular arm used gene knockdown rather than patient material
    and whose central claim is about peroxisomal disorders generally, so it is
    recorded here as a lead rather than as a pathograph node.
  proposed_experiments:
  - experiment_id: exp_ald_adrenal_cholesterol_trafficking
    name: Adrenocortical cholesterol-trafficking test of the lysosomal trapping model
    description: >-
      Differentiate ABCD1-null and isogenic corrected iPSC into adrenocortical
      organoids, measure lysosomal cholesterol load, mitochondrial cholesterol
      delivery, and ACTH-stimulated cortisol output, then test whether
      cyclodextrin restores steroidogenesis. Pair with single-cell
      transcriptomics of post-mortem ALD adrenal cortex to check that the
      organoid signature is present in patients.
  evidence:
  - reference: PMID:38034003
    reference_title: X-linked adrenoleukodystrophy and primary adrenal insufficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The pathogenesis of X-ALD related PAI is still unclear
    explanation: >-
      A dedicated review of adrenal involvement in ALD states the mechanistic
      gap directly rather than leaving it to be inferred.
  - reference: PMID:38034003
    reference_title: X-linked adrenoleukodystrophy and primary adrenal insufficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      there is no evidence so far that HCT can change the course of PAI in ALD
      patients
    explanation: >-
      Documents that the treatment which halts the cerebral arm leaves the
      adrenal arm untouched. Note the source frames this as absence of evidence
      plus absence of reported reversals, not as a demonstrated mechanistic
      dissociation.
  - reference: PMID:36971991
    reference_title: "Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Abcd1 knockout mice, HPCD injections reduced cholesterol and VLCFA
      sequestration in the brain and adrenal cortex.
    explanation: >-
      The first pharmacological rescue of adrenal function in an ALD model, and
      the only currently testable mechanistic proposal for the adrenal arm.
      Single study, mouse and knockdown-cell evidence only.
- discussion_id: ald_ferroptosis_emerging
  prompt: >-
    Is ferroptosis a distinct mode of cell death in cerebral ALD lesions, or
    are the iron and lipid-peroxidation findings a downstream marker of
    demyelination already under way?
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  attaches_to:
  - pathophysiology#Inflammatory cerebral demyelination
  - pathophysiology#Oxidative stress
  rationale: >-
    Iron accumulation, myelin peroxidation, and raised ACSL4 have been reported
    in perilesional white matter, which would place an iron-dependent death
    pathway alongside the innate and adaptive immune arms already curated here.
    The finding rests on one study with no intervention arm and no replication,
    and the authors themselves phrase the conclusion as implicating rather than
    demonstrating ferroptosis, so it is recorded as an emerging hypothesis
    rather than as a pathophysiology node. Directionality is the specific
    problem: perilesional tissue sits at the advancing edge of an active
    lesion, so the markers are equally consistent with ferroptosis driving
    lesion expansion and with its being a consequence of ongoing myelin
    breakdown.
  proposed_experiments:
  - experiment_id: exp_ald_ferroptosis_inhibitor_two_hit
    name: Ferroptosis inhibition in the two-hit cerebral ALD mouse model
    description: >-
      Treat Abcd1-knockout mice carrying the cuprizone plus experimental
      autoimmune encephalomyelitis cerebral phenotype with ferrostatin-1 or
      liproxstatin-1 against vehicle, reading out lesion volume, quantitative
      susceptibility mapping for iron, and ACSL4 and GPX4 immunohistochemistry.
      Reduced demyelination under inhibition would establish direction; no
      effect would place the iron findings downstream.
  evidence:
  - reference: PMID:41732993
    reference_title: "Evidence of Iron Accumulation in Cerebral Adrenoleukodystrophy: A Potential Novel Disease Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In perilesional white matter, increases in myelin peroxidation and
      Acyl-CoA synthetase long-chain family member 4 are observed.
    explanation: >-
      Reports the imaging and tissue findings behind the ferroptosis proposal.
      A single study, framed by its authors as implicating rather than
      establishing the pathway.
notes: >-
  Initial curation emphasizes the ABCD1-VLCFA mechanism, cerebral
  demyelination, adrenal insufficiency, and early-transplant management from
  currently cached literature.

📚

References & Deep Research

References

1

PMID:20301491

X-Linked Adrenoleukodystrophy.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of adrenoleukodystrophy. Core disease mechanisms, molecular and cellular path...

Asta Scientific Corpus Retrieval 20 citations 2026-04-14T16:27:15.704259

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of adrenoleukodystrophy. Core disease mechanisms, molecular and cellular path...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] 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: 0.474) > 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.

[2] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.448) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[3] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
Year: 2024
Venue: International Journal For Multidisciplinary Research
URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
DOI: 10.36948/ijfmr.2024.v06i03.19194
Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
Evidence snippets:
Snippet 1 (score: 0.445) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[4] Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

Authors: C. Casasnovas, M. Ruiz, A. Schlüter, A. Naudí, S. Fourcade et al.
Year: 2019
Venue: Neurotherapeutics
URL: https://www.semanticscholar.org/paper/58ebde4f86151c0fa04ddc9d0df6ee2b13cc24ea
DOI: 10.1007/s13311-019-00735-2
PMID: 31077039
PMCID: 6985062
Citations: 41
Influential citations: 1
Summary: A positive signal is suggested for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose, and candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials are suggested.
Evidence snippets:
Snippet 1 (score: 0.441) > X-Adrenoleukodystrophy (X-ALD) is the most frequently inherited leukodystrophy, with a minimum incidence of 1 in 14,700 live births [1]. The gene mutated in the disease (ABCD1) encodes the ALD protein (ALDP), a peroxisomal transporter that imports very long-chain fatty acids (VLCFA) into the peroxisome for degradation [2,3]. Elevated plasma VLCFA is a pathognomonic biomarker for this disorder, although it lacks predictive value for disease severity or progression [4]. Different phenotypes have been described in X-ALD. Virtually all patients who reach adulthood develop the most frequent phenotype, adrenomyeloneuropathy (AMN), in their third and fourth decades of life. The initial symptoms are limited to the spinal cord and peripheral nerves. Patients develop progressive spastic paraparesis, sensory ataxia with impaired vibration sense, sphincter dysfunction, pain in the legs, and impotence [5]. Neurophysiological findings reveal axonal neuropathy and disturbances in evoked potentials [6]. Brain magnetic resonance imaging (MRI) results are often abnormal, mainly affecting the corticospinal tract [7]. Approximately 80% of patients suffer from adrenocortical insufficiency [5]. Women carriers often present mild myelopathy after the fourth decade of life [8]. The most severe disease phenotype, cerebral childhood adrenoleukodystrophy (cALD), presents rapidly progressive inflammatory brain demyelination with a lethal outcome unless diagnosed early and treated with hematopoietic bone marrow transplant [9] or the new available hematopoietic stem cell therapy [10]. > At present, there is no satisfactory treatment for patients with AMN [11]. Oxidative stress is a major factor driving X-ALD pathogenesis [12][13][14][15][16][17] and appears very early in life [12].

[5] 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: 0.441) > 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].

[6] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
Year: 2025
Venue: Pathophysiology
URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
DOI: 10.3390/pathophysiology32010009
PMID: 39982365
PMCID: 12077258
Citations: 25
Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
Evidence snippets:
Snippet 1 (score: 0.436) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[7] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

Authors: Nagwa Gaboon, B. Banaganapalli, K. Nasser, M. Razeeth, Mosab S. Alsaedi et al.
Year: 2019
Venue: Saudi Journal of Biological Sciences
URL: https://www.semanticscholar.org/paper/f1f1341fd61e31f39a5129e7c80ff67cd0b6fb0f
DOI: 10.1016/j.sjbs.2019.10.001
PMID: 31889854
PMCID: 6933272
Citations: 17
Influential citations: 1
Summary: Genetic defects in RMND1 gene alters the mitochondrial energy metabolism leading to the accumulation of ceramide, and subsequently promote dysregulated apoptosis and tissue necrosis in kidneys, this study suggests.
Evidence snippets:
Snippet 1 (score: 0.430) > One of the recently identified nuclear genes involved in mitochondrial respiratory chain deficiencies is RMND1 (Required for Meiotic Nuclear Division protein 1) (Garcia-Diaz et al., 2012;Janer et al., 2012). It has been demonstrated that various novel and common recessive mutations in RMND1 are associated with multiple phenotypes characterized by delayed maturation of vision, developmental delay, dilated cardiomyopathy, deafness and neurological defects (Gupta et al., 2016), renal tubular acidosis type 4 presented as hyponatraemia and hyperkalaemia and cystic/hypoplastic kidneys (Ng et al., 2016). Likewise, complex clinical spectrum of patients with RMND1 mutations is emerging with infantile encephalomyopathy with lactic acidosis (Garcia-Diaz et al., 2012;Casey et al., 2016) to a less severe form of developmental delay, hypotonia, renal disease and congenital sensorineural deafness (Janer et al., 2015). Therefore, molecular screening of RMND1 gene will help identify the inheritance mode of causative genetic mutations in patients with renal and or neurological defects. > MIDs have complex etiologies with underlying cross talk of inter and intra molecular signaling. Hence, metabolomic studies on these patients could provide a better understanding of the interconnectivity between genetic and molecular networks (Davies, 2018). Metabolomic profiling examines the metabolic changes in body fluids driven from cellular processes to understand the onset and pathogenesis of disease phenotype (Abbiss et al., 2019). Metabolomics analyzes metabolites by either targeted or untargeted approaches. The untargeted approach involves hypothesis free surveying of hundreds of thousands of small molecule metabolites for discovering novel mechanisms or pathways, whereas the targeted one refers to measuring predefined sets of metabolites, typically focusing on a few pathways of interest (Kalim and Rhee, 2017). The specific relationship between inherited mutations in mitochondrial proteins and their functional impacts in terms of metabolic defects in chronic kidney disease (CKD) is not yet well characterized.

[8] 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: 0.430) > 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

[9] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
Year: 2025
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
DOI: 10.3389/fendo.2025.1501305
PMID: 40070584
PMCID: 11893406
Citations: 11
Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
Evidence snippets:
Snippet 1 (score: 0.430) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.

[10] 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: 0.423) > 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.

[11] Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases

Authors: Valentina La Cognata, Giovanna Morello, S. Cavallaro
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/fd3586b07f23e89cece5c7ea2abc6fddd871568e
DOI: 10.3390/ijms22094820
PMID: 34062930
PMCID: 8125201
Citations: 35
Summary: How omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches are discussed, bringing us closer to the goal of personalized medicine in neurology.
Evidence snippets:
Snippet 1 (score: 0.421) > Neurodegenerative diseases (NDs) are debilitating and largely untreatable conditions characterized by a decline of nervous system functions due to a progressive neuronal loss in the brain and spinal cord. The classification of NDs is still usually based on the clinical presentation (i.e., cognitive decline, speech difficulties and motor impairment), anatomical regions and cell types affected [1,2]. As the exact molecular mechanisms of the disease pathogenesis and progression remain unclear, the clinical management of NDs is limited to simply mitigating neurodegeneration and relieving symptoms rather than reversing the damage done [1,3,4]. > NDs can be either monogenic, like Huntington disease, or complex, highly heterogeneous-including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)-and characterized by variable molecular phenotypes, progression courses or patterns of neuro-biochemical markers of brain damage, making patient counseling, disease management and pharmaceutical care particularly difficult [3]. The underlying mechanisms of these complex NDs are polyfactorial and depend on the combination of genetic, biological and environmental factors. The presence of abnormal protein conformations, excessive immune response and inflammation, impaired nucleocytoplasmic transport, mitochondrial dysfunction, neuronal dysfunction and autophagy are common features of neurodegeneration [5,6]. However, despite considerable efforts, the molecular mechanisms involved in the complex phenotype of NDs are still largely unknown, and current treatments cannot prevent the development of the disease. The failure of the majority of neurological clinical trials, especially during Phase 3, can be attributed to a lack of efficacy, probably due to the incorrect selection of the target population [7,8]. A full readout of ND conditions to support stratified medicine. From the genome onwards, information gathered from all omics molecular layers of NDs conditions will aid researchers and clinicians to better characterize the disease's molecular heterogeneity, stratify patients by novel biomarkers and improve therapeutic outcomes.

[12] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.417) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[13] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.417) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[14] Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research

Authors: Guillermo Roberto Jiménez-Pareyón, J. Cristóbal-Luna, Y. García-Martínez, Cynthia Garfias-Noguez, Morayma Ramírez-Damián et al.
Year: 2025
Venue: Microorganisms
URL: https://www.semanticscholar.org/paper/6c92b8101905064ff4e4e8585f4fa86ebfac0826
DOI: 10.3390/microorganisms13122718
PMID: 41471921
PMCID: 12735313
Summary: A review of current evidence on the GBA’s involvement in conditions such as Alzheimer’s disease, Parkinson’s disease, depression, and anxiety examines how psychobiotics may modulate neuroinflammation, oxidative stress, and neurotransmitter signaling, thereby contributing to cognitive and emotional regulation.
Evidence snippets:
Snippet 1 (score: 0.416) > Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive deterioration of the central or peripheral nervous system. These diseases cause morphological changes in the brain, leading to significant cognitive or motor impairments, debilitating symptoms, and a reduced quality of life [16]. NDs involve complex cellular responses triggered by the accumulation of pathologically altered brain substances, ultimately resulting in irreversible loss of neuronal populations [17]. > The pathophysiology of NDs is multifactorial and intricate, involving cellular, molecular, and genetic mechanisms. These include protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, cytoskeletal abnormalities, disrupted synaptic networks, neuronal death, aberrant cell proliferation, neuroinflammation, demyelination, altered axonal transport, dysregulated energy metabolism, and abnormal modifications of DNA or RNA [16,[18][19][20][21][22]. > NDs can be classified according to several criteria, such as their etiology, the molecular mechanisms involved, and the anatomical regions affected [23]. Although multiple classification systems exist, these disorders often share overlapping cellular and molecular mechanisms [24], which complicates efforts to categorize them into a single scheme. From a mechanistic perspective, NDs commonly exhibit recurring pathological events such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and the accumulation of misfolded proteins [16]. Recent classification systems increasingly emphasize the type of protein aggregates for diagnostic accuracy [25]. Clinically, NDs can also be classified clinically based on predominant symptoms, such as movement disorders in PD and Huntington's disease, cognitive deficits in AD, or a combination of both [12,26,27]. This approach allows for a better understanding of their heterogeneity and facilitates the development of more specific therapeutic strategies. Among the spectrum of neurodegenerative conditions, AD and PD are the most prevalent and extensively studied (Figure 1).

[15] Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes

Authors: M. Lang, P. Pramstaller, I. Pichler
Year: 2022
Venue: Molecular Neurodegeneration
URL: https://www.semanticscholar.org/paper/61554668ad754c9cf8ea032cfb48773e91592041
DOI: 10.1186/s13024-022-00555-7
PMID: 35842725
PMCID: 9288732
Citations: 20
Summary: The activation of MiT transcription factors through genetic and pharmacological approaches have shown encouraging results at ameliorating PD-related phenotypes in in vitro and in vivo models and focus on the role of the MiT pathway and its potential as pharmacological target against PD.
Evidence snippets:
Snippet 1 (score: 0.414) > PD is a NDD that is characterized by pathological protein misfolding and aggregation as well as organellar dysfunction leading to neuronal cell death, which causes motor-and non-motor symptoms. Mitochondrial homeostasis and quality control have historically been recognized as crucial contributors to PD pathogenesis, and several aspects of mitochondrial biology are impaired in PD patients and models. In addition, defects of macroautophagy and the ALP have been observed in cell and animal models of PD as well as PD patients' brains, where constitutive autophagy is indispensable for adaptation to stress and energy deficiency. Various mechanisms are involved in the interplay between PD-related mitochondrial defects, lysosomal dysfunctions, and protein aggregate formations. The specific disease cascade in PD patients may differ based on which genetic and environmental factors act as main triggers. As outlined in this review, the functions of various organellar compartments are tightly linked and influence each other. Connections between these organelles are constituted among others by mitophagy, metabolite homeostasis, organellar dynamics, including exo-and endocytosis, and cellular signaling cascades, including Ca 2+ signaling, This may lead to the recognition of druggable proteins that can influence MiT activation and help to develop pharmacologically relevant molecules that would increase lysosomal biogenesis and boost degradation pathways in the brain of affected individuals. Such treatment strategies would best be applied before debilitating effects of the disease are being experienced. This, however, will require parallel efforts for the development of early diagnostic methods that would help to recognize biological malfunctions before the damage to cells is too extensive and clinical symptoms appear. Only if diseasealtering treatment options are applied before significant brain regions are impacted by the disease, it will be possible to achieve truly meaningful effects. Overall, more work will be needed to bridge basic knowledge of the main pathways affecting PD with their potential clinical applications, but recent developments in the field have uncovered promising pathways, including the here described approaches, that may provide disease-altering therapies against PD.

[16] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Authors: Kyung-Yil Lee
Year: 2022
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
DOI: 10.1186/s13578-022-00920-5
PMID: 36384812
PMCID: 9668226
Citations: 9
Influential citations: 1
Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
Evidence snippets:
Snippet 1 (score: 0.411) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[17] Potential cerebrospinal fluid metabolomic biomarkers and early prediction model for Parkinson’s disease

Authors: Yifan Zhang, Yuexin Yan, Xiangxu Kong, Haijun Zhang, Shengyuan Su
Year: 2025
Venue: Frontiers in Aging Neuroscience
URL: https://www.semanticscholar.org/paper/57fa4686dec3091fc3019e6771a6d0db010c8e23
DOI: 10.3389/fnagi.2025.1582362
PMID: 40520532
PMCID: 12163037
Summary: The differential expression of CSF metabolites reveals early cellular metabolic changes, providing insights for early diagnosis and monitoring PD progression, and shows a bidirectional causal relationship exists between genetically determined PD susceptibility and metabolites.
Evidence snippets:
Snippet 1 (score: 0.409) > Cerebrospinal fluid (CSF), which directly interacts with brain cells, offers an accurate reflection of the underlying molecular mechanisms of PD. While the α-synuclein seed amplification assay in CSF demonstrates high sensitivity and specificity, it reflects only part of the disease pathology, highlighting the need for additional biomarkers to fully characterize PD (Postuma and Berg, 2016). CSF metabolomics, through the mapping and quantification of various small-molecule metabolites, provides a comprehensive insight into cellular metabolism and neurotransmitter alterations (Stoessel et al., 2018). With recent advancements in liquid chromatography-mass spectrometry (LC-MS/ MS), key biomarkers related to lipid metabolism, polyamines, amino acids, and purine metabolism have garnered increasing attention (Trezzi et al., 2017;Kremer et al., 2021). > This study aims to explore the differences in various metabolites, particularly lipid metabolites, at different clinical stages of PD (including healthy controls, prodromal PD, and clinically diagnosed PD patients) using CSF metabolomics as a data-driven source. The study further aims to predict the risk of PD progression. The objectives of this study are as follows: (1) to identify cerebrospinal metabolic biomarkers at different stages of PD progression; (2) to assess the reliability of predictive models by developing a clinical risk model for PD; (3) to link lipid metabolism biomarkers with clinical manifestations to provide clinical utility; (4) to uncover potential mechanisms underlying PD progression through metabolic biomarkers and associated molecular pathways; (5) MR analysis was conducted using publicly available genome-wide association data to evaluate the causal relationship between differential metabolites and Parkinson's disease.

[18] Evolution of adrenoleukodystrophy model systems

Authors: R. Montoro, V. Heine, S. Kemp, M. Engelen
Year: 2020
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/f56613d587d84a989445ee01f3a8911ac13192e5
DOI: 10.1002/jimd.12357
PMID: 33373044
PMCID: 8248356
Citations: 7
Summary: An overview of the different ALD modeling strategies from single‐celled to multicellular organisms and from in vitro to in vivo approaches is provided, and how emerging iPSC‐derived technologies could improve the understanding of this highly complex disorder is introduced.
Evidence snippets:
Snippet 1 (score: 0.409) > X-linked adrenoleukodystrophy (ALD; OMIM: 300100) is the most common peroxisomal neurometabolic disorder characterized by a spectrum of symptoms and defined by mutations in the ABCD1 gene. 1 Nearly all men and ~80% of women develop slowly progressive spinal cord disease known as adrenomyeloneuropathy (AMN). In men, features range from adrenal insufficiency to progressive inflammatory cerebral demyelination (cerebral ALD), which are very rare findings among women with ALD. 1,2 oreover, given that monozygotic twins can have a disconcordant disease course, a combination of rare genetic modifiers, epigenetic, and environmental factors have been hypothesized to impact the disease outcome. 3,4 he complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. > Model systems have been extensively employed in an attempt to understand the pathophysiology of ALD (Table 1). Truncation of the ABCD1 gene has been the most used strategy to experimentally model ALD. in vitro studies provided us the majority of knowledge on ABCD1 biochemistry and function, but obviously come with limitations when trying to understand a neurological dysfunction. In addition, the creation of animal knockout models of the human ABCD1 ortholog has advanced our insights into disease mechanisms. However, animal models also failed to fully recapitulate the complex neurodegenerative etiology of ALD. Recently, the ALD field has begun to explore the potentials of induced pluripotent stem cell (iPSC)-based modeling approaches. The first patient iPSC studies presented biochemical hallmarks of ALD in disease-relevant cell types of the nervous system. 5,6 ach model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this disorder.

[19] 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: 0.406) > 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

[20] ABCD2 Is a Direct Target of β-Catenin and TCF-4: Implications for X-Linked Adrenoleukodystrophy Therapy

Authors: Chul-Yong Park, H. Kim, Jiho Jang, Hyunji Lee, Jae Souk Lee et al.
Year: 2013
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/4e8884c5bcd9270af9e657b160a20a22e7d39ca0
DOI: 10.1371/journal.pone.0056242
PMID: 23437103
PMCID: 3578850
Citations: 17
Summary: Results demonstrate for the first time the direct regulation of ABCD2 by β-catenin and TCF-4 in X-linked adrenoleukodystrophy.
Evidence snippets:
Snippet 1 (score: 0.404) > X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by mutations or large deletions of one or more exons in the ABCD1 gene located in Xq28, which encodes the peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D member 1 (ABCD1), also known as adrenoleukodystrophy protein (ALDP) [1,2]. X-ALD has an incidence of 1 in 17,000 males, and has several clinical phenotypes, namely severe childhood cerebral form (CCALD, early-onset type), a slowly progressive form called adrenomyeloneuropathy (AMN, late-onset type), and adult cerebral form (ACALD) [3,4]. Currently, no therapeutic drugs for X-ALD are available, although gene correction of autologous hematopoietic stem cell with a wild-type version of the ABCD1 gene by a lentiviral vector has been shown to provide clinical benefit in X-ALD patients [5]. ABCD1 transports very long chain fatty acids (VLCFAs; those with more than 22 carbon atoms) or their CoA derivatives across the peroxisomal membrane for b-oxidation. Recently, it was demonstrated that human ABCD1 was able to transport VLCFA-CoA into the peroxisome in a yeast system [6]. Dysfunction of ABCD1 results in increased levels of saturated (C24:0 and C26:0) and monounsaturated (C26:1) VLCFAs in the plasma and tissues of X-ALD patients, due to the reduced boxidation of VLCFAs in peroxisomes [7]. Recently, we first reported the generation of X-ALD patient-derived induced pluripotent stem (iPS) cell models [8]. Generated X-ALD iPS cells were successfully differentiated into oligodendrocytes, the main cell type affected by the disease, and notably revealed the underlying pathophysiology which had not been observed in patients' fibroblasts or animal models.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of adrenoleukodystrophy. Core disease mechanisms, molecular and cellular path...

Relevant Papers

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

[2] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

[3] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

[4] Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study

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

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[7] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

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

[9] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

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

[11] Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases

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[13] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

[14] Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research

[15] Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes

[16] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

[17] Potential cerebrospinal fluid metabolomic biomarkers and early prediction model for Parkinson’s disease

[18] Evolution of adrenoleukodystrophy model systems

[19] Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

[20] ABCD2 Is a Direct Target of β-Catenin and TCF-4: Implications for X-Linked Adrenoleukodystrophy Therapy

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