Adrenoleukodystrophy

Summary

Adrenoleukodystrophy (MONDO:0018544) is a disease caused by ABCD1 (GenCC Definitive), with 8 cohort genes and 48 clinical trials. The dominant Reactome pathway is Fatty acid metabolism (3 cohort genes). Top therapeutic interventions include cyclophosphamide anhydrous, albumin human, and alemtuzumab.

At a glance

• Prevalence: 1-9 / 1 000 000 (Norway) [Orphanet-validated]
• Causal gene: ABCD1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 1,551
• Phenotypes (HPO): 36
• Clinical trials: 48

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.8	Norway	Validated
Prevalence at birth	1-9 / 1 000 000	0.8	Israel	Validated
Prevalence at birth	1-5 / 10 000	2.0639	United States	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000572	Visual loss	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0000752	Hyperactivity	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001730	Progressive hearing impairment	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0002311	Incoordination	Very frequent (80-99%)
HP:0002312	Clumsiness	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002385	Paraparesis	Very frequent (80-99%)
HP:0003474	Somatic sensory dysfunction	Very frequent (80-99%)
HP:0004302	Functional motor deficit	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Very frequent (80-99%)
HP:0007199	Progressive spastic paraparesis	Very frequent (80-99%)
HP:0008969	Leg muscle stiffness	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000011	Neurogenic bladder	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000734	Disinhibition	Frequent (30-79%)
HP:0000846	Adrenal insufficiency	Frequent (30-79%)
HP:0001123	Visual field defect	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0002381	Aphasia	Frequent (30-79%)
HP:0002516	Increased intracranial pressure	Frequent (30-79%)
HP:0002839	Urinary bladder sphincter dysfunction	Frequent (30-79%)
HP:0003154	Increased circulating ACTH level	Frequent (30-79%)
HP:0008768	Inappropriate sexual behavior	Frequent (30-79%)
HP:0011733	Abnormality of adrenal physiology	Frequent (30-79%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0000802	Impotence	Occasional (5-29%)
HP:0003470	Paralysis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adrenoleukodystrophy
Mondo ID	MONDO:0018544
MeSH	D000326
OMIM	300100
Orphanet	43
DOID	DOID:10588
ICD-11	1085655586
NCIT	C61252
UMLS	C0162309
MedGen	57667
GARD	0005758
MedDRA	10051260
NORD	736
Is cancer (heuristic)	no

Also known as: ABCD1 deficiency · adrenoleukodystrophy · adrenoleukodystrophy, X-linked · adrenoleukodystrophy, X-linked recessive · adrenomyeloneuropathy, adult · adrenomyeloneuropathy, adult, X-linked recessive · ALD · Bronze-Schilder disease · diffuse cerebral sclerosis of Schilder · Siemerling-Creutzfeldt disease · X-ALD · X-Linked Adrenoleukodystrophy · X-linked adrenoleukodystrophy · X-linked ALD

Data availability: 1,551 ClinVar variants · 42 ClinGen variant curations · 4 GenCC gene-disease records · 44 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Subtypes (3): X-linked cerebral adrenoleukodystrophy, 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

600 retrieved; paginated sample, class counts are floors:

271 likely benign, 99 uncertain significance, 93 pathogenic, 49 conflicting classifications of pathogenicity, 33 likely pathogenic, 25 pathogenic/likely pathogenic, 21 benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1037296	NM_000033.4(ABCD1):c.1247C>G (p.Thr416Arg)	ABCD1	Pathogenic	criteria provided, single submitter
1039444	NM_000033.4(ABCD1):c.598G>A (p.Asp200Asn)	ABCD1	Pathogenic	criteria provided, single submitter
1059218	NM_000033.4(ABCD1):c.234_242del (p.Arg80_Leu82del)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067768	NM_000033.4(ABCD1):c.873G>C (p.Glu291Asp)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068643	NM_000033.4(ABCD1):c.965T>C (p.Leu322Pro)	ABCD1	Pathogenic	criteria provided, single submitter
1068922	NM_000033.4(ABCD1):c.788_820del (p.Pro263_Ala273del)	ABCD1	Pathogenic	criteria provided, single submitter
1068950	NM_000033.4(ABCD1):c.2030dup (p.Gly678fs)	ABCD1	Pathogenic	criteria provided, single submitter
1071003	NC_000023.10:g.(?153002601)(153002715_?)del	ABCD1	Pathogenic	criteria provided, single submitter
1071153	NC_000023.10:g.(?152990722)(153009189_?)del	ABCD1	Pathogenic	criteria provided, single submitter
1071155	NC_000023.10:g.(?153001789)(153009189_?)del	ABCD1	Pathogenic	criteria provided, single submitter
1072284	NM_000033.4(ABCD1):c.668_900+291del	ABCD1	Pathogenic	criteria provided, single submitter
1072765	NM_000033.4(ABCD1):c.697del (p.Ala233fs)	ABCD1	Pathogenic	criteria provided, single submitter
1072909	NM_000033.4(ABCD1):c.1138G>T (p.Glu380Ter)	ABCD1	Pathogenic	criteria provided, single submitter
1073715	NM_000033.4(ABCD1):c.1501_1510del (p.Met501fs)	ABCD1	Pathogenic	criteria provided, single submitter
1075470	NM_000033.4(ABCD1):c.36dup (p.Asn13fs)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075691	NM_000033.4(ABCD1):c.785C>G (p.Ser262Trp)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076654	NM_000033.4(ABCD1):c.589_590del (p.Leu197fs)	ABCD1	Pathogenic	criteria provided, single submitter
11292	NM_000033.4(ABCD1):c.871G>A (p.Glu291Lys)	ABCD1	Pathogenic	criteria provided, single submitter
11294	NM_000033.4(ABCD1):c.1635-2A>G	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11297	NM_000033.4(ABCD1):c.443A>G (p.Asn148Ser)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11298	NM_000033.4(ABCD1):c.520T>G (p.Tyr174Asp)	ABCD1	Pathogenic	no assertion criteria provided
11299	NM_000033.4(ABCD1):c.796G>A (p.Gly266Arg)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11301	NM_000033.4(ABCD1):c.1252C>T (p.Arg418Trp)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11302	NM_000033.4(ABCD1):c.1390C>T (p.Arg464Ter)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11303	NM_000033.4(ABCD1):c.1415_1416del (p.Gln472fs)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11306	NM_000033.4(ABCD1):c.1552del (p.Arg518fs)	ABCD1	Pathogenic	criteria provided, single submitter
11307	NM_000033.4(ABCD1):c.1552C>T (p.Arg518Trp)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11308	NM_000033.4(ABCD1):c.1634+1G>A	ABCD1	Pathogenic	no assertion criteria provided
11309	NM_000033.4(ABCD1):c.1792_1793del (p.Met598fs)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11310	NM_000033.4(ABCD1):c.1817C>T (p.Ser606Leu)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 8 · 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
SCD	Limited	Autosomal recessive	adrenoleukodystrophy
SLC22A5	Limited	Autosomal recessive	adrenoleukodystrophy	9

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
SLC22A5	Orphanet:158	Systemic primary carnitine deficiency
NAA10	Orphanet:276432	Ogden syndrome
NAA10	Orphanet:568	Microphthalmia, Lenz type
FAM50A	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	gencc,clinvar
SCD	HGNC:10571	ENSG00000099194	O00767	Stearoyl-CoA desaturase	gencc
SLC22A5	HGNC:10969	ENSG00000197375	O76082	Organic cation/carnitine transporter 2	gencc
NAA10	HGNC:18704	ENSG00000102030	P41227	N-alpha-acetyltransferase 10	clinvar
FAM50A	HGNC:18786	ENSG00000071859	Q14320	Protein FAM50A	clinvar
CTAG1B	HGNC:2491	ENSG00000184033	P78358	Cancer/testis antigen 1	clinvar
PLXNB3-AS1	HGNC:40454	ENSG00000232725		PLXNB3 antisense RNA 1	clinvar
PLXNB3	HGNC:9105	ENSG00000198753	Q9ULL4	Plexin-B3	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.
SCD	Stearoyl-CoA desaturase	Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates.
SLC22A5	Organic cation/carnitine transporter 2	Sodium-ion dependent, high affinity carnitine transporter.
NAA10	N-alpha-acetyltransferase 10	Catalytic subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase activity.
FAM50A	Protein FAM50A	Probably involved in the regulation of pre-mRNA splicing.
PLXNB3	Plexin-B3	Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.62

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	2	19.4×	0.018
Enzyme (other)	2	3.0×	0.278
Antibody/Immunoglobulin	1	3.6×	0.325
Other/Unknown	3	0.7×	0.919

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
SCD	Enzyme (other)	yes	1.14.19.1	FADS-1_CS, Acyl-CoA_DS
SLC22A5	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
NAA10	Enzyme (other)	yes	2.3.1.255	GNAT_dom, Acyl_CoA_acyltransferase, Ard1-like
FAM50A	Other/Unknown	no		XAP5, FAM50A/XAP5_C
CTAG1B	Other/Unknown	no		CTAG/Pcc1
PLXNB3-AS1	Other/Unknown	no
PLXNB3	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom

Expression context

Cohort genes with no expression data: 0.

6 cohort genes 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
sural nerve	2
primordial germ cell in gonad	2
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
inferior vagus X ganglion	1
subthalamic nucleus	1
superior vestibular nucleus	1
gastrocnemius	1
mucosa of transverse colon	1
muscle of leg	1
apex of heart	1
lower esophagus muscularis layer	1
adenohypophysis	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
testis	1
muscle layer of sigmoid colon	1
C1 segment of cervical spinal cord	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
SCD	289	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, superior vestibular nucleus
SLC22A5	235	ubiquitous	marker	gastrocnemius, mucosa of transverse colon, muscle of leg
NAA10	288	ubiquitous	marker	right hemisphere of cerebellum, apex of heart, lower esophagus muscularis layer
FAM50A	283	ubiquitous	marker	sural nerve, adenohypophysis, stromal cell of endometrium
CTAG1B	36	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, testis
PLXNB3-AS1	133		yes	sural nerve, primordial germ cell in gonad, muscle layer of sigmoid colon
PLXNB3	133	ubiquitous	yes	C1 segment of cervical spinal cord, tibial nerve, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCD	3,176
NAA10	2,579
SLC22A5	1,492
CTAG1B	1,470
ABCD1	1,181
PLXNB3	1,117
FAM50A	836
PLXNB3-AS1	0

Intra-cohort edges

A	B	Sources
ABCD1	PLXNB3	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTAG1B	P78358	23
ABCD1	P33897	14
NAA10	P41227	12
SLC22A5	O76082	3
FAM50A	Q14320	2
SCD	O00767	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLXNB3	Q9ULL4	81.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 8 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fatty acid metabolism	3	78.8×	2e-04	ABCD1, SCD, SLC22A5
Metabolism of lipids	3	18.9×	0.006	ABCD1, SCD, SLC22A5
Disorders of transmembrane transporters	2	55.7×	0.007	ABCD1, SLC22A5
Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP)	1	1142.0×	0.007	SLC22A5
Defective ABCD1 causes ALD	1	1142.0×	0.007	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	380.7×	0.017	ABCD1
Linoleic acid (LA) metabolism	1	228.4×	0.020	ABCD1
NR1H2 & NR1H3 regulate gene expression linked to lipogenesis	1	228.4×	0.020	SCD
Beta-oxidation of very long chain fatty acids	1	175.7×	0.020	ABCD1
Carnitine shuttle	1	152.3×	0.020	SLC22A5
SLC-mediated transport of organic cations	1	152.3×	0.020	SLC22A5
R-HSA-549132	1	152.3×	0.020	SLC22A5
alpha-linolenic acid (ALA) metabolism	1	142.8×	0.020	ABCD1
Peroxisomal lipid metabolism	1	134.3×	0.020	ABCD1
ABC transporters in lipid homeostasis	1	120.2×	0.020	ABCD1
Other semaphorin interactions	1	120.2×	0.020	PLXNB3
Metabolism	3	7.0×	0.020	ABCD1, SCD, SLC22A5
Class I peroxisomal membrane protein import	1	103.8×	0.021	ABCD1
ABC transporter disorders	1	87.8×	0.023	ABCD1
Fatty acyl-CoA biosynthesis	1	87.8×	0.023	SCD
NR1H2 and NR1H3-mediated signaling	1	78.8×	0.024	SCD
Transport of small molecules	2	10.1×	0.026	ABCD1, SLC22A5
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	63.4×	0.027	SCD
Activation of gene expression by SREBF (SREBP)	1	51.9×	0.032	SCD
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	43.1×	0.037	SCD
SLC transporter disorders	1	40.8×	0.037	SLC22A5
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	39.4×	0.037	SCD
Protein localization	1	38.1×	0.037	ABCD1
R-HSA-425366	1	36.2×	0.038	SLC22A5
Epigenetic regulation by WDR5-containing histone modifying complexes	1	30.9×	0.043	SCD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
unsaturated fatty acid biosynthetic process	2	185.2×	0.003	ABCD1, SCD
monounsaturated fatty acid biosynthetic process	1	2407.4×	0.006	SCD
positive regulation of protein refolding	1	2407.4×	0.006	NAA10
negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric	1	2407.4×	0.006	NAA10
peroxisomal membrane transport	1	1203.7×	0.006	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1203.7×	0.006	ABCD1
positive regulation of intestinal epithelial structure maintenance	1	1203.7×	0.006	SLC22A5
sodium-dependent organic cation transport	1	1203.7×	0.006	SLC22A5
(R)-carnitine transport	1	1203.7×	0.006	SLC22A5
(R)-carnitine transmembrane transport	1	802.5×	0.007	SLC22A5
positive regulation of unsaturated fatty acid biosynthetic process	1	802.5×	0.007	ABCD1
carnitine transport	1	601.9×	0.007	SLC22A5
sterol homeostasis	1	601.9×	0.007	ABCD1
negative regulation of lamellipodium assembly	1	481.5×	0.007	PLXNB3
quaternary ammonium group transport	1	481.5×	0.007	SLC22A5
long-chain fatty acid import into peroxisome	1	481.5×	0.007	ABCD1
response to symbiotic bacterium	1	401.2×	0.007	SLC22A5
regulation of fatty acid beta-oxidation	1	401.2×	0.007	ABCD1
long-chain fatty acid catabolic process	1	401.2×	0.007	ABCD1
myelin maintenance	1	401.2×	0.007	ABCD1
regulation of mitochondrial depolarization	1	401.2×	0.007	ABCD1
tRNA threonylcarbamoyladenosine metabolic process	1	401.2×	0.007	CTAG1B
carnitine transmembrane transport	1	401.2×	0.007	SLC22A5
fatty acid elongation	1	343.9×	0.007	ABCD1
very long-chain fatty acid catabolic process	1	343.9×	0.007	ABCD1
positive regulation of fatty acid beta-oxidation	1	218.9×	0.011	ABCD1
fatty acid derivative biosynthetic process	1	218.9×	0.011	ABCD1
regulation of cellular response to oxidative stress	1	185.2×	0.012	ABCD1
regulation of oxidative phosphorylation	1	172.0×	0.013	ABCD1
neuron projection maintenance	1	160.5×	0.013	ABCD1

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Elivaldogene Autotemcel	Approved (phase 4)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine, Albumin Human, Busulfan, Leriglitazone, Lipoic Acid, Alpha, Pioglitazone, Vitamin E.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCD	1	1
ABCD1	0	0
SLC22A5	0	0
NAA10	0	0
FAM50A	0	0
CTAG1B	0	0
PLXNB3-AS1	0	0
PLXNB3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MK-8245	1	SCD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC22A5	97	Functional:79, ADMET:18
SCD	83	Binding:74, ADMET:8, Unclassified:1
NAA10	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
SCD	1.14.19.1	stearoyl-CoA 9-desaturase
NAA10	2.3.1.255, 2.3.1.258, 2.3.1.48	N-terminal amino-acid Nalpha-acetyltransferase NatA, N-terminal methionine Nalpha-acetyltransferase NatE, histone acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MK-8245	1	SCD

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	1	SCD
C	Druggable family + PDB, no drug	3	ABCD1, SLC22A5, NAA10
D	Druggable family + AlphaFold only, no drug	1	PLXNB3
E	Difficult family or no structure, no drug	3	FAM50A, CTAG1B, PLXNB3-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCD1	0	—
SLC22A5	97	—
NAA10	2	—
FAM50A	0	—
CTAG1B	0	—
PLXNB3-AS1	0	—
PLXNB3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 48.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	27
PHASE2	5
PHASE1/PHASE2	5
PHASE2/PHASE3	4
PHASE1	4
PHASE3	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
NCT03196765	PHASE1/PHASE2	WITHDRAWN	Safety, Pharmacokinetics and Pharmacodynamics of NV1205 in Pediatric Male Subjects With Adrenoleukodystrophy
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03864523	PHASE2	COMPLETED	Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy
NCT05200104	PHASE2	WITHDRAWN	Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD)
NCT05394064	PHASE1/PHASE2	TERMINATED	A Study to Evaluate Administration of SBT101 Gene Therapy in Adult Patients With Adrenomyeloneuropathy (AMN)
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
NCT01787578	PHASE1	WITHDRAWN	Safety and Pharmacodynamic Study of Sobetirome in X-Linked Adrenoleukodystrophy (X-ALD)
NCT02595489	PHASE1	COMPLETED	A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy
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
NCT03727555	Not specified	RECRUITING	IT and IV Lentiviral Gene Therapy for X-ALD
NCT03789721	Not specified	RECRUITING	Adrenoleukodystrophy National Registry Study
NCT04675749	Not specified	RECRUITING	Quality of Life in Women with X-linked Adrenoleukodystrophy
NCT04925349	Not specified	RECRUITING	Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
NCT05911919	Not specified	NOT_YET_RECRUITING	Validation of a Prognostic Biomarker Using Brain Diffusion MRI in X-linked Adrenoleukodystrophy
NCT05939232	Not specified	RECRUITING	Registry of X-linked Adrenoleukodystrophy
NCT06178120	Not specified	RECRUITING	Disease Progression in Women With X-linked Adrenoleukodystrophy
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
NCT01165060	Not specified	COMPLETED	The Effect of Bezafibrate on the Level of Very Long Chain Fatty Acids (VLCFA) in X-linked Adrenoleukodystrophy (X-ALD)
NCT01594853	Not specified	COMPLETED	Exercise Study of Function and Pathology for Women With X-linked Adrenoleukodystrophy
NCT02204904	Not specified	TERMINATED	Observational Study to Evaluate Allogeneic HSCT Outcomes for Cerebral Adrenoleukodystrophy (CALD)
NCT02233257	Not specified	NO_LONGER_AVAILABLE	Expanded Access for Lorenzo’s Oil (GTO/GTE) in Adrenoleukodystrophy
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

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
BEZAFIBRATE	3	1
DEXPRAMIPEXOLE	3	1
INTERFERON BETA	3	1
LERIGLITAZONE	3	1
GLYCERYL TRIERUCATE	2	2
GLYCERYL TRIOLEATE	2	2
SOBETIROME	2	2
CHEMBL1201343	0	1
CHEMBL3739769	0	1