Chronic primary adrenal insufficiency

Summary

Chronic primary adrenal insufficiency (MONDO:0015129) is a disease (an umbrella term covering 8 Mondo subtypes) with 1 cohort gene (1 GWAS associations across 4 studies) and 2 clinical trials. Top therapeutic interventions include prednisone.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 1
• GWAS associations: 1
• ClinVar variants: 2
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.4	Europe	Validated
Point prevalence	1-5 / 10 000	14	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	chronic primary adrenal insufficiency
Mondo ID	MONDO:0015129
MeSH	D000224
OMIM	240200
Orphanet	101959
DOID	DOID:13774
NCIT	C26689
SNOMED CT	373662000
UMLS	C0001403
MedGen	1324
GARD	0019803
MedDRA	10001130
Is cancer (heuristic)	no

Also known as: adrenal gland hypofunction · chronic adrenocorticoid insufficiency · CPAI · hypoadrenocorticism familial · hypoadrenocorticism, familial · primary adrenal insufficiency, chronic · primary hypoadrenalism

Data availability: 2 ClinVar variants · 1 GWAS association (4 studies).

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenocortical insufficiency › primary adrenal insufficiency › chronic primary adrenal insufficiency

Related subtypes (1): acute adrenal insufficiency

Subtypes (8): adrenocortical hypofunction, chronic primary congenital, familial adrenal hypoplasia with absent pituitary luteinizing hormone, familial glucocorticoid deficiency, triple-A syndrome, X-linked adrenal hypoplasia congenita, inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency, congenital adrenal hyperplasia, autoimmune primary adrenal insufficiency

Genetics & variants

GWAS landscape

1 GWAS associations across 4 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs530430768	3e-11	MYL10 - CUX1	C	3.21

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477344	Verma A	2024	1,500	448,550	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479903	Verma A	2024	439	121,074	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481596	Verma A	2024	439	121,074	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435730	Zhou W	2018	364	405,386	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs530430768	7	101762936	C>T	0	intergenic_variant	MYL10 - CUX1	3e-11	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11310	NM_000033.4(ABCD1):c.1817C>T (p.Ser606Leu)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11311	NM_000033.4(ABCD1):c.1820del (p.Gly607fs)	ABCD1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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	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

Drugs indicated for this disease

5 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Cortisone Acetate	Approved (phase 4)
Dexamethasone	Approved (phase 4)
Fludrocortisone Acetate	Approved (phase 4)
Prednisolone	Approved (phase 4)
Prednisone	Approved (phase 4)
Prasterone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Hydrocortisone, Hydrocortisone Cypionate.

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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00975078	PHASE4	COMPLETED	Test Predicting Adrenal Insufficiency in Volunteers Under Prednisone Treatment
NCT00001180	Not specified	COMPLETED	Dose Response Relationship for Single Doses of Corticotropin Releasing Hormone (CRH) in Normal Volunteers and in Patients With Adrenal Insufficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PREDNISONE	4	1
CHEMBL15720	0	1