Idiopathic achalasia

Summary

Idiopathic achalasia (MONDO:0019635) is a disease with 3 cohort genes and 15 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 10
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.77	Worldwide	Validated
Point prevalence	1-9 / 100 000	8	Worldwide	Validated
Annual incidence	1-9 / 100 000	1.59	Italy	Validated
Annual incidence	1-9 / 1 000 000	0.73	Iceland	Validated
Annual incidence	1-9 / 1 000 000	0.3	Singapore	Validated
Annual incidence	1-9 / 1 000 000	0.39	Korea, Republic of	Validated
Annual incidence	1-9 / 100 000	1.63	Canada	Validated
Point prevalence	1-5 / 10 000	10.82	Canada	Validated
Point prevalence	1-9 / 100 000	6.29	Korea, Republic of	Validated
Point prevalence	1-5 / 10 000	13.5	Ireland	Validated
Point prevalence	1-9 / 100 000	8.7	Iceland	Validated
Point prevalence	1-9 / 100 000	1.8	Singapore	Validated
Prevalence at birth	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0002015	Dysphagia	Very frequent (80-99%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0012387	Bronchitis	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0002100	Recurrent aspiration pneumonia	Occasional (5-29%)
HP:0004395	Malnutrition	Occasional (5-29%)
HP:0030828	Wheezing	Occasional (5-29%)
HP:0031085	Decreased prealbumin level	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	idiopathic achalasia
Mondo ID	MONDO:0019635
Orphanet	930
ICD-11	396058084
SNOMED CT	715192004
UMLS	C0859976
MedGen	798339
GARD	0005708
MedDRA	10036669
Is cancer (heuristic)	no

Also known as: achalasia cardia · idiopathic achalasia of esophagus · idiopathic achalasia of oesophagus · primary achalasia

Data availability: 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › upper digestive tract disorder › esophageal disorder › achalasia › idiopathic achalasia

Related subtypes (1): achalasia, familial esophageal

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · 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
CRLF1	Supportive	Autosomal recessive	idiopathic achalasia	6
NANOS1	Supportive	Autosomal recessive	idiopathic achalasia	3
NOS1	Supportive	Autosomal recessive	idiopathic achalasia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NANOS1	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CRLF1	Orphanet:1545	Crisponi syndrome
CRLF1	Orphanet:157820	Cold-induced sweating syndrome
CRLF1	Orphanet:930	Idiopathic achalasia
NOS1	Orphanet:930	Idiopathic achalasia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NANOS1	HGNC:23044	ENSG00000188613	Q8WY41	Nanos homolog 1	gencc
CRLF1	HGNC:2364	ENSG00000006016	O75462	Cytokine receptor-like factor 1	gencc
NOS1	HGNC:7872	ENSG00000089250	P29475	Nitric oxide synthase 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NANOS1	Nanos homolog 1	May act as a translational repressor which regulates translation of specific mRNAs by forming a complex with PUM2 that associates with the 3’-UTR of mRNA targets.
CRLF1	Cytokine receptor-like factor 1	In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development.
NOS1	Nitric oxide synthase 1	Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.246
Scaffold/PPI	1	5.8×	0.246
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NANOS1	Transcription factor	no		Nanos/Xcar2, Znf_nanos-typ, Nanos_sf
CRLF1	Antibody/Immunoglobulin	yes	1.1.1.105	FN3_dom, Ig-like_fold, Growth/epo_recpt_lig-bind
NOS1	Scaffold/PPI	no	1.14.13.39	Flavdoxin-like, OxRdtase_FAD/NAD-bd, PDZ

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skeletal muscle tissue of biceps brachii	2
oocyte	1
secondary oocyte	1
popliteal artery	1
right coronary artery	1
tibial artery	1
biceps brachii	1
body of tongue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NANOS1	199	ubiquitous	yes	secondary oocyte, oocyte, skeletal muscle tissue of biceps brachii
CRLF1	227	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
NOS1	167	broad	marker	body of tongue, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOS1	2,835
NANOS1	1,112
CRLF1	589

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOS1	P29475	121
NANOS1	Q8WY41	1
CRLF1	O75462	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-27 signaling	1	519.1×	0.005	CRLF1
Nitric oxide stimulates guanylate cyclase	1	407.9×	0.005	NOS1
IL-6-type cytokine receptor ligand interactions	1	317.2×	0.005	CRLF1
ROS and RNS production in phagocytes	1	167.9×	0.007	NOS1
Ion homeostasis	1	102.0×	0.010	NOS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic signaling by nitric oxide	1	5617.3×	0.005	NOS1
positive regulation of sodium ion transmembrane transport	1	5617.3×	0.005	NOS1
negative regulation of serotonin uptake	1	1872.4×	0.005	NOS1
positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	1872.4×	0.005	NOS1
regulation of postsynaptic membrane potential	1	1404.3×	0.005	NOS1
cerebellar neuron development	1	1404.3×	0.005	NANOS1
negative regulation of calcium ion transport into cytosol	1	1123.5×	0.005	NOS1
positive regulation of the force of heart contraction	1	1123.5×	0.005	NOS1
L-arginine catabolic process	1	936.2×	0.005	NOS1
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	936.2×	0.005	NOS1
negative regulation of potassium ion transport	1	624.1×	0.007	NOS1
negative regulation of calcium ion transport	1	561.7×	0.007	NOS1
regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	561.7×	0.007	NOS1
negative regulation of motor neuron apoptotic process	1	510.7×	0.007	CRLF1
obsolete nitric oxide mediated signal transduction	1	432.1×	0.007	NOS1
regulation of cardiac muscle contraction by calcium ion signaling	1	432.1×	0.007	NOS1
multicellular organismal response to stress	1	432.1×	0.007	NOS1
regulation of sodium ion transport	1	312.1×	0.009	NOS1
epithelial cell migration	1	312.1×	0.009	NANOS1
regulation of cardiac muscle contraction	1	295.6×	0.009	NOS1
striated muscle contraction	1	280.9×	0.009	NOS1
nitric oxide biosynthetic process	1	234.1×	0.009	NOS1
mRNA destabilization	1	224.7×	0.009	NANOS1
post-transcriptional regulation of gene expression	1	216.1×	0.009	NANOS1
negative regulation of blood pressure	1	216.1×	0.009	NOS1
myoblast fusion	1	200.6×	0.009	NOS1
tissue homeostasis	1	187.2×	0.009	NANOS1
xenobiotic catabolic process	1	187.2×	0.009	NOS1
cell surface receptor signaling pathway via STAT	1	187.2×	0.009	CRLF1
ureteric bud development	1	151.8×	0.011	CRLF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NOS1	SAPROPTERIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOS1	10	4
NANOS1	0	0
CRLF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SAPROPTERIN	4	NOS1
CHLORZOXAZONE	4	NOS1
TILARGININE	3	NOS1
GW-274150	2	NOS1
KD7040	2	NOS1
PIMAGEDINE	2	NOS1
AMINOTHIAZOLE	2	NOS1
PRAXADINE	2	NOS1
L-NAME	2	NOS1
NITROARGININE	1	NOS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
NOS1	238	Binding:234, Functional:2, Unclassified:1, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CRLF1	1.1.1.105	all-trans-retinol dehydrogenase (NAD+)
NOS1	1.14.13.39	nitric-oxide synthase (NADPH)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NOS1	238

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
SAPROPTERIN	4	NOS1
CHLORZOXAZONE	4	NOS1
TILARGININE	3	NOS1
GW-274150	2	NOS1
KD7040	2	NOS1
PIMAGEDINE	2	NOS1
AMINOTHIAZOLE	2	NOS1
PRAXADINE	2	NOS1
L-NAME	2	NOS1
NITROARGININE	1	NOS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NOS1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CRLF1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NANOS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NANOS1	0	—
CRLF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	12
PHASE3	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06189859	PHASE3	RECRUITING	Electrosurgical Modes for Endoscopic Submucosal Dissection in Peroral Endoscopic Esophageal Myotomy
NCT01560559	PHASE3	COMPLETED	Peroral Endoscopic Myotomy for Primary Esophageal Achalasia
NCT03784365	PHASE3	UNKNOWN	Single-Versus Multiple-dose Antimicrobial Prophylaxis for Peroral Endoscopic Myotomy in Achalasia
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06290882	Not specified	ACTIVE_NOT_RECRUITING	Endoscopic Versus Robotic Myotomy for Treatment of Achalasia
NCT07022886	Not specified	ACTIVE_NOT_RECRUITING	INCIDENCE, PREVALENCE AND OVERALL RISK OF ESOPHAGEAL CANCER IN ACHALASIA: A PROPENSITY-MATCHED POPULATION-BASED STUDY FROM A LARGE MULTICENTER DATABASE
NCT07167355	Not specified	NOT_YET_RECRUITING	Comparison of Balloon Dilatation and Per Oral Endoscopic Myotomy in Children With Achalasia Cardia
NCT07399652	Not specified	RECRUITING	Artificial Intelligence-Guided Detection of Blood Vessels to Enhance Safety in Third-Space Endoscopic Procedures
NCT02025790	Not specified	UNKNOWN	POEM Versus Pneumatic Dilatation in Achalasia Cardia
NCT03186248	Not specified	COMPLETED	Randomized Clinical Trial Comparing Short Versus Long Oesophageal Myotomy in POEM for Achalasia Cardia.
NCT03438838	Not specified	UNKNOWN	Randomised Trial Between LHM Alone Vs LHM With Anterior Fundoplication In Achalasia Cardia
NCT04951739	Not specified	COMPLETED	To Investigate the Incidence of Reflux in Patients After Per-oral Endoscopic Myotomy in Achalasia Cardia Patients
NCT05729971	Not specified	COMPLETED	Nasogastric Tube After Laparoscopic Heller-Dor Myotomy
NCT07177222	Not specified	COMPLETED	Compare the Quality of Life of Patients With Achalasia Cardia (AC) After Laparoscopic and Open Esophagocardiomyotomy.
NCT07451301	Not specified	COMPLETED	Serum Anti-enteric Neuronal Antibodies in Patients With Achalasia and Their Association With Clinical Profiles