Alternating hemiplegia of childhood

Summary

Alternating hemiplegia of childhood (MONDO:0016241) is a disease with 2 cohort genes and 8 clinical trials. Top therapeutic interventions include oxybate, oxygen, and triheptanoin.

At a glance

• Prevalence: 1-9 / 1 000 000 (Denmark) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 3
• Phenotypes (HPO): 65
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.94	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0002579	Gastrointestinal dysmotility	Very frequent (80-99%)
HP:0011024	Abnormality of the gastrointestinal tract	Very frequent (80-99%)
HP:0012194	Episodic hemiplegia	Very frequent (80-99%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0000577	Exotropia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002273	Tetraparesis	Frequent (30-79%)
HP:0003270	Abdominal distention	Frequent (30-79%)
HP:0011499	Mydriasis	Frequent (30-79%)
HP:0012332	Abnormal autonomic nervous system physiology	Frequent (30-79%)
HP:0012547	Abnormal involuntary eye movements	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0031284	Flushing	Frequent (30-79%)
HP:0200136	Oral-pharyngeal dysphagia	Frequent (30-79%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000975	Hyperhidrosis	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002263	Exaggerated cupid’s bow	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002344	Progressive neurologic deterioration	Occasional (5-29%)
HP:0002483	Bulbar signs	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alternating hemiplegia of childhood
Mondo ID	MONDO:0016241
MeSH	C536589
OMIM	104290
Orphanet	2131
DOID	DOID:0050635
ICD-11	301329822
NCIT	C35261
SNOMED CT	230466004
UMLS	C0338488
MedGen	90925
GARD	0000011
NORD	758
Is cancer (heuristic)	no

Also known as: adrenal hypoplasia congenita · AHC · alternating hemiplegia · alternating hemiplegia of childhood · alternating hemiplegia syndrome · childhood alternating hemiplegia · congenital adrenal gland hypoplasia · congenital adrenal Hypoplasia · paediatric alternating hemiplegia · pediatric alternating hemiplegia

Data availability: 3 ClinVar variants · 2 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › hemiplegia › alternating hemiplegia of childhood

Subtypes (3): alternating hemiplegia of childhood 1, X-linked adrenal hypoplasia congenita, alternating hemiplegia of childhood 2

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

3 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
667000	NM_152296.5(ATP1A3):c.2330T>A (p.Ile777Asn)	ATP1A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
979069	NM_000702.4(ATP1A2):c.2809del (p.Arg937fs)	ATP1A2	Likely pathogenic	criteria provided, single submitter
1705824	NM_152296.5(ATP1A3):c.998G>A (p.Cys333Tyr)	ATP1A3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 39 · Orphanet: 7 · 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
ATP1A3	Definitive	Autosomal dominant	alternating hemiplegia of childhood 2	20
ATP1A2	Strong	Autosomal dominant	alternating hemiplegia of childhood 1	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A2	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A2	Orphanet:569	Familial or sporadic hemiplegic migraine
ATP1A3	Orphanet:1171	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
ATP1A3	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A3	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A3	Orphanet:71517	Rapid-onset dystonia-parkinsonism

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	gencc,clinvar
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A2	Sodium/potassium-transporting ATPase subunit alpha-2	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral globus pallidus	1
superior vestibular nucleus	1
trigeminal ganglion	1
cortical plate	1
primary visual cortex	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A2	262	broad	marker	lateral globus pallidus, trigeminal ganglion, superior vestibular nucleus
ATP1A3	129	broad	marker	superior frontal gyrus, primary visual cortex, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A3	3,876
ATP1A2	2,679

Intra-cohort edges

A	B	Sources
ATP1A2	ATP1A3	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP1A3	P13637	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A2	P50993	88.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Ion transport by P-type ATPases	2	207.6×	1e-04	ATP1A2, ATP1A3
Ion homeostasis	2	203.9×	1e-04	ATP1A2, ATP1A3
Potential therapeutics for SARS	2	114.2×	2e-04	ATP1A2, ATP1A3
Cardiac conduction	2	108.8×	2e-04	ATP1A2, ATP1A3
Ion channel transport	2	96.0×	2e-04	ATP1A2, ATP1A3
Muscle contraction	2	77.2×	3e-04	ATP1A2, ATP1A3
SARS-CoV Infections	2	55.4×	5e-04	ATP1A2, ATP1A3
Viral Infection Pathways	2	30.8×	0.001	ATP1A2, ATP1A3
Transport of small molecules	2	25.1×	0.002	ATP1A2, ATP1A3
Infectious disease	2	24.8×	0.002	ATP1A2, ATP1A3
Disease	2	13.1×	0.006	ATP1A2, ATP1A3

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to glycoside	2	2407.4×	8e-06	ATP1A2, ATP1A3
cell communication by electrical coupling involved in cardiac conduction	2	1404.3×	1e-05	ATP1A2, ATP1A3
sodium ion export across plasma membrane	2	1053.2×	1e-05	ATP1A2, ATP1A3
cellular response to steroid hormone stimulus	2	1053.2×	1e-05	ATP1A2, ATP1A3
intracellular potassium ion homeostasis	2	991.3×	1e-05	ATP1A2, ATP1A3
intracellular sodium ion homeostasis	2	766.0×	1e-05	ATP1A2, ATP1A3
potassium ion import across plasma membrane	2	366.4×	5e-05	ATP1A2, ATP1A3
proton transmembrane transport	2	312.1×	7e-05	ATP1A2, ATP1A3
olfactory cortex development	1	8426.0×	7e-04	ATP1A2
regulation of glutamate uptake involved in transmission of nerve impulse	1	4213.0×	0.001	ATP1A2
negative regulation of calcium ion transmembrane transport	1	4213.0×	0.001	ATP1A2
negative regulation of striated muscle contraction	1	2808.7×	0.002	ATP1A2
negative regulation of heart contraction	1	2106.5×	0.002	ATP1A2
amygdala development	1	1404.3×	0.003	ATP1A2
regulation of striated muscle contraction	1	1053.2×	0.003	ATP1A2
response to potassium ion	1	1053.2×	0.003	ATP1A2
positive regulation of heart contraction	1	1053.2×	0.003	ATP1A2
regulation of muscle contraction	1	842.6×	0.003	ATP1A2
L-ascorbic acid metabolic process	1	766.0×	0.003	ATP1A2
locomotion	1	766.0×	0.003	ATP1A2
neurotransmitter uptake	1	702.2×	0.003	ATP1A2
neuronal action potential propagation	1	702.2×	0.003	ATP1A2
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	ATP1A2
regulation of respiratory gaseous exchange by nervous system process	1	648.1×	0.003	ATP1A2
negative regulation of cytosolic calcium ion concentration	1	648.1×	0.003	ATP1A2
relaxation of cardiac muscle	1	648.1×	0.003	ATP1A2
regulation of resting membrane potential	1	648.1×	0.003	ATP1A3
membrane repolarization	1	648.1×	0.003	ATP1A2
regulation of smooth muscle contraction	1	601.9×	0.003	ATP1A2
regulation of cardiac muscle cell contraction	1	561.7×	0.003	ATP1A2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
ATP1A2	OMEPRAZOLE
ATP1A3	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A2	5	4
ATP1A3	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A2, ATP1A3
DIGOXIN	4	ATP1A2, ATP1A3
DIGITOXIN	4	ATP1A2, ATP1A3
LANSOPRAZOLE	4	ATP1A2, ATP1A3
ROSTAFUROXIN	2	ATP1A2, ATP1A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP1A2	49	Binding:49
ATP1A3	45	Binding:45

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
OMEPRAZOLE	4	ATP1A2, ATP1A3
DIGOXIN	4	ATP1A2, ATP1A3
DIGITOXIN	4	ATP1A2, ATP1A3
LANSOPRAZOLE	4	ATP1A2, ATP1A3
ROSTAFUROXIN	2	ATP1A2, ATP1A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ATP1A2, ATP1A3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00931164	PHASE1/PHASE2	COMPLETED	Sodium Oxybate in Patients With Alternating Hemiplegia of Childhood (AHC-SO)
NCT02408354	PHASE2	COMPLETED	Pilot Study, Comparative, Single-center, Randomized, Crossover, Double-blind, Against Placebo, Testing the Effectiveness of Triheptanoin Oil in Alternating Hemiplegia of Childhood
NCT06248645	PHASE2	COMPLETED	Oxygen as an Acute Treatment in Alternating Hemiplegia of Childhood
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT03857607	Not specified	UNKNOWN	Natural History Study of ATP1A3-related Disease
NCT04020848	Not specified	COMPLETED	Observe Alternating Hemiplegia of Childhood (OBSERV-AHC) Study
NCT04944927	Not specified	COMPLETED	HEmiplegia Arrhythmia Retrospective Trial
NCT06007521	Not specified	COMPLETED	Validation of a Clinical Assessment Scale Specific to Alternating Hemiplegia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OXYBATE	4	3
OXYGEN	4	1
TRIHEPTANOIN	4	1