X-linked cerebral adrenoleukodystrophy

Summary

X-linked cerebral adrenoleukodystrophy (MONDO:0010247) is a disease caused by ABCD1 (GenCC Definitive), with 1 cohort gene and 31 clinical trials. Top therapeutic interventions include cyclophosphamide anhydrous, albumin human, and alemtuzumab.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ABCD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 50
• Clinical trials: 31

Clinical features

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0002196	Myelopathy	Very frequent (80-99%)
HP:0007162	Diffuse demyelination of the cerebral white matter	Very frequent (80-99%)
HP:0007305	CNS demyelination	Very frequent (80-99%)
HP:0008163	Decreased circulating cortisol level	Very frequent (80-99%)
HP:0008167	Very long chain fatty acid accumulation	Very frequent (80-99%)
HP:0008207	Primary adrenal insufficiency	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002143	Abnormality of the spinal cord	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002518	Abnormal periventricular white matter morphology	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0004359	Abnormal circulating fatty-acid concentration	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0012501	Abnormality of the brainstem white matter	Frequent (30-79%)
HP:0007034	Generalized hyperreflexia	Occasional (5-29%)
HP:0000026	Male hypogonadism	Occasional (5-29%)
HP:0000317	Facial myokymia	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0003089	Hamstring contractures	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0010527	Astereognosia	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0030222	Visual agnosia	Occasional (5-29%)
HP:0031993	Hoffmann sign	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)
HP:0045084	Limb myoclonus	Occasional (5-29%)
HP:0000618	Blindness	Very rare (<1-4%)
HP:0002540	Inability to walk	Very rare (<1-4%)
HP:0031358	Vegetative state	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked cerebral adrenoleukodystrophy
Mondo ID	MONDO:0010247
Orphanet	139396
ICD-11	1105019687
UMLS	C2026514
MedGen	1708324
GARD	0009412
Is cancer (heuristic)	no

Also known as: adrenoleukodystrophy · adrenoleukodystrophy childhood cerebral form · adrenoleukodystrophy X-linked cerebral form · ALD · ALD childhood cerebral form · childhood cerebral ALD · childhood-onset cerebral X-linked adrenoleukodystrophy · X-linked cerebral adrenoleukodystrophy

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records · 44 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › adrenoleukodystrophy › X-linked cerebral adrenoleukodystrophy

Related subtypes (2): adrenomyeloneuropathy, isolated adrenal insufficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679830	NM_000033.4(ABCD1):c.125del (p.Pro42fs)	ABCD1	Likely pathogenic	criteria provided, single submitter
218422	NM_000033.4(ABCD1):c.1816T>C (p.Ser606Pro)	ABCD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABCD1	Definitive	X-linked	X-linked cerebral adrenoleukodystrophy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCD1	1,181

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	5710.0×	0.003	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	1903.3×	0.004	ABCD1
Linoleic acid (LA) metabolism	1	1142.0×	0.004	ABCD1
Beta-oxidation of very long chain fatty acids	1	878.5×	0.004	ABCD1
alpha-linolenic acid (ALA) metabolism	1	713.8×	0.004	ABCD1
Peroxisomal lipid metabolism	1	671.8×	0.004	ABCD1
ABC transporters in lipid homeostasis	1	601.0×	0.004	ABCD1
Class I peroxisomal membrane protein import	1	519.1×	0.004	ABCD1
ABC transporter disorders	1	439.2×	0.004	ABCD1
Protein localization	1	190.3×	0.009	ABCD1
Disorders of transmembrane transporters	1	139.3×	0.011	ABCD1
Fatty acid metabolism	1	131.3×	0.011	ABCD1
ABC-family protein mediated transport	1	121.5×	0.011	ABCD1
Metabolism of lipids	1	31.6×	0.038	ABCD1
Transport of small molecules	1	25.1×	0.045	ABCD1
Disease	1	13.1×	0.081	ABCD1
Metabolism	1	11.6×	0.086	ABCD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peroxisomal membrane transport	1	8426.0×	1e-03	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	8426.0×	1e-03	ABCD1
positive regulation of unsaturated fatty acid biosynthetic process	1	5617.3×	1e-03	ABCD1
sterol homeostasis	1	4213.0×	1e-03	ABCD1
long-chain fatty acid import into peroxisome	1	3370.4×	1e-03	ABCD1
regulation of fatty acid beta-oxidation	1	2808.7×	1e-03	ABCD1
long-chain fatty acid catabolic process	1	2808.7×	1e-03	ABCD1
myelin maintenance	1	2808.7×	1e-03	ABCD1
regulation of mitochondrial depolarization	1	2808.7×	1e-03	ABCD1
fatty acid elongation	1	2407.4×	1e-03	ABCD1
very long-chain fatty acid catabolic process	1	2407.4×	1e-03	ABCD1
positive regulation of fatty acid beta-oxidation	1	1532.0×	0.001	ABCD1
fatty acid derivative biosynthetic process	1	1532.0×	0.001	ABCD1
regulation of cellular response to oxidative stress	1	1296.3×	0.001	ABCD1
regulation of oxidative phosphorylation	1	1203.7×	0.001	ABCD1
neuron projection maintenance	1	1123.5×	0.001	ABCD1
negative regulation of reactive oxygen species biosynthetic process	1	991.3×	0.002	ABCD1
fatty acid homeostasis	1	936.2×	0.002	ABCD1
alpha-linolenic acid metabolic process	1	887.0×	0.002	ABCD1
peroxisome organization	1	802.5×	0.002	ABCD1
very long-chain fatty acid metabolic process	1	766.0×	0.002	ABCD1
linoleic acid metabolic process	1	702.2×	0.002	ABCD1
unsaturated fatty acid biosynthetic process	1	648.1×	0.002	ABCD1
long-chain fatty acid biosynthetic process	1	443.5×	0.002	ABCD1
negative regulation of cytokine production involved in inflammatory response	1	421.3×	0.002	ABCD1
fatty acid beta-oxidation	1	374.5×	0.003	ABCD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	15
PHASE2/PHASE3	4
PHASE2	4
PHASE1/PHASE2	3
PHASE3	2
PHASE1	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05003648	PHASE4	ACTIVE_NOT_RECRUITING	Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy
NCT00007020	PHASE3	COMPLETED	Compassionate Treatment of Patients With Inborn Errors of Bile Acid Metabolism With Cholic Acid
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT00545597	PHASE3	TERMINATED	A Phase III Trial of Lorenzo’s Oil in Adrenomyeloneuropathy
NCT02961803	PHASE2/PHASE3	COMPLETED	MD1003-AMN MD1003 in Adrenomyeloneuropathy
NCT03231878	PHASE2/PHASE3	COMPLETED	A Clinical Study to Evaluate the Efficacy and Safety of MIN-102 (IMP) in Male AMN Patients.
NCT04303416	PHASE2/PHASE3	COMPLETED	Plasma Exchange With Albumin in AMN Patients
NCT00004418	PHASE2	TERMINATED	Effect of Glycerol Trierucate on Clinical Course of Adrenoleukodystrophy
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT02559830	PHASE1/PHASE2	UNKNOWN	Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT05200104	PHASE2	WITHDRAWN	Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD)
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT02698579	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03789721	Not specified	RECRUITING	Adrenoleukodystrophy National Registry Study
NCT04925349	Not specified	RECRUITING	Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT00004442	Not specified	TERMINATED	Study of Bile Acids in Patients With Peroxisomal Disorders
NCT00004450	Not specified	COMPLETED	Randomized Study of Beta Interferon and Thalidomide in Patients With Adrenoleukodystrophy
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT00278044	Not specified	UNKNOWN	Clinical Study and Gene Mutation Analysis of Adrenoleukodystrophy in Taiwanese Children
NCT02204904	Not specified	TERMINATED	Observational Study to Evaluate Allogeneic HSCT Outcomes for Cerebral Adrenoleukodystrophy (CALD)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02948062	Not specified	WITHDRAWN	Early Diagnosis Of Childhood Cerebral ALD
NCT02952482	Not specified	COMPLETED	Newborn Screening for Adrenoleukodystrophy
NCT04090268	Not specified	UNKNOWN	Precision Exercise in Children With Malignant Hemopathies
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOPHOSPHAMIDE ANHYDROUS	4	2
ALBUMIN HUMAN	4	1
ALEMTUZUMAB	4	1
BUSULFAN	4	1
CHENODIOL	4	1
CHOLIC ACID	4	1
CLOFARABINE	4	1
HYDROXYUREA	4	1
PRAMIPEXOLE	4	1
URSODIOL	4	1
DEXPRAMIPEXOLE	3	1
INTERFERON BETA	3	1
LERIGLITAZONE	3	1
GLYCERYL TRIERUCATE	2	2
GLYCERYL TRIOLEATE	2	2
CHEMBL1201343	0	1