Familial or sporadic hemiplegic migraine

Summary

Familial or sporadic hemiplegic migraine (MONDO:0018925) is a disease with 4 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Europe	Validated
Point prevalence	1-5 / 10 000	10	Denmark	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002077	Migraine with aura	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0011153	Focal motor seizure	Very frequent (80-99%)
HP:0011157	Focal sensory seizure	Very frequent (80-99%)
HP:0032900	Focal manual automatism seizure	Frequent (30-79%)
HP:0032901	Focal pedal automatism seizure	Frequent (30-79%)
HP:0200149	CSF lymphocytic pleiocytosis	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000575	Scotoma	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001269	Hemiparesis	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002181	Cerebral edema	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0002922	Increased CSF protein concentration	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0010835	Dissociated sensory loss	Frequent (30-79%)
HP:0011172	Complex febrile seizure	Frequent (30-79%)
HP:0011468	Facial tics	Frequent (30-79%)
HP:0012229	CSF pleocytosis	Frequent (30-79%)
HP:0012508	Metamorphopsia	Frequent (30-79%)
HP:0030786	Photopsia	Frequent (30-79%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002301	Hemiplegia	Occasional (5-29%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0007209	Facial paralysis	Occasional (5-29%)
HP:0007979	Gaze-evoked horizontal nystagmus	Occasional (5-29%)
HP:0008959	Distal upper limb muscle weakness	Occasional (5-29%)
HP:0010544	Vertical nystagmus	Occasional (5-29%)
HP:0010829	Impaired temperature sensition	Occasional (5-29%)
HP:0010833	Spontaneous pain sensation	Occasional (5-29%)
HP:0011199	EEG with generalized sharp slow waves	Occasional (5-29%)
HP:0012044	Seesaw nystagmus	Occasional (5-29%)
HP:0031179	Nuchal rigidity	Occasional (5-29%)
HP:0032044	Decreased vigilance	Occasional (5-29%)
HP:0032506	Alien limb phenomenon	Occasional (5-29%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0002133	Status epilepticus	Very rare (<1-4%)
HP:0003392	First dorsal interossei muscle weakness	Very rare (<1-4%)
HP:0011196	EEG with focal sharp waves	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial or sporadic hemiplegic migraine
Mondo ID	MONDO:0018925
Orphanet	569
ICD-10-CM	G43.4
ICD-11	1957063016
SNOMED CT	59292006
UMLS	C0270862
MedGen	78740
GARD	0010768
NORD	1979
Is cancer (heuristic)	no

Also known as: familial or sporadic hemiplegic migraine · Hemiplegic Migraine · hemiplegic migraine

Data availability: 4 GenCC gene-disease records · 9 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › migraine disorder › migraine with aura › familial or sporadic hemiplegic migraine

Related subtypes (1): migraine with brainstem aura

Subtypes (2): familial hemiplegic migraine, sporadic hemiplegic migraine

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: 80 · Orphanet: 23 · 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
ATP1A2	Definitive	Autosomal dominant	migraine, familial hemiplegic, 2	19
CACNA1A	Strong	Autosomal dominant	migraine, familial hemiplegic, 1	23
SCN1A	Strong	Autosomal dominant	migraine, familial hemiplegic, 3	20
PRRT2	Supportive	Autosomal dominant	familial or sporadic hemiplegic migraine	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
PRRT2	Orphanet:306	Self-limited infantile epilepsy
PRRT2	Orphanet:36387	Genetic epilepsy with febrile seizure plus
PRRT2	Orphanet:569	Familial or sporadic hemiplegic migraine
PRRT2	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
PRRT2	Orphanet:98810	Paroxysmal non-kinesigenic dyskinesia
PRRT2	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
ATP1A2	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A2	Orphanet:569	Familial or sporadic hemiplegic migraine

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc
PRRT2	HGNC:30500	ENSG00000167371	Q7Z6L0	Proline-rich transmembrane protein 2	gencc
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
PRRT2	Proline-rich transmembrane protein 2	As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system.
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.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	2	55.8×	0.001
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
PRRT2	Other/Unknown	no		CD225/Dispanin_fam, CD225/Dispanin
ATP1A2	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.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
primary visual cortex	1
lateral globus pallidus	1
superior vestibular nucleus	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
PRRT2	202	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ATP1A2	262	broad	marker	lateral globus pallidus, trigeminal ganglion, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A2	2,679
SCN1A	2,287
PRRT2	1,545
CACNA1A	346

Intra-cohort edges

A	B	Sources
ATP1A2	PRRT2	string_interaction
ATP1A2	SCN1A	string_interaction
PRRT2	SCN1A	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A2	P50993	88.25
PRRT2	Q7Z6L0	51.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiac conduction	2	72.5×	0.006	SCN1A, ATP1A2
Muscle contraction	2	51.4×	0.006	SCN1A, ATP1A2
Presynaptic depolarization and calcium channel opening	1	317.2×	0.024	CACNA1A
Interaction between L1 and Ankyrins	1	122.8×	0.040	SCN1A
Phase 0 - rapid depolarisation	1	115.3×	0.040	SCN1A
Regulation of insulin secretion	1	73.2×	0.042	CACNA1A
Ion transport by P-type ATPases	1	69.2×	0.042	ATP1A2
Ion homeostasis	1	68.0×	0.042	ATP1A2
Integration of energy metabolism	1	58.6×	0.043	CACNA1A
L1CAM interactions	1	40.1×	0.054	SCN1A
Potential therapeutics for SARS	1	38.1×	0.054	ATP1A2
Ion channel transport	1	32.0×	0.059	ATP1A2
Transmission across Chemical Synapses	1	25.4×	0.069	CACNA1A
SARS-CoV Infections	1	18.5×	0.087	ATP1A2
Axon guidance	1	15.1×	0.092	SCN1A
Neuronal System	1	14.8×	0.092	CACNA1A
Nervous system development	1	14.3×	0.092	SCN1A
Viral Infection Pathways	1	10.3×	0.121	ATP1A2
Transport of small molecules	1	8.4×	0.133	ATP1A2
Infectious disease	1	8.3×	0.133	ATP1A2
Developmental Biology	1	4.8×	0.212	SCN1A
Disease	1	4.4×	0.222	ATP1A2
Metabolism	1	3.9×	0.237	CACNA1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neuronal action potential propagation	2	702.2×	2e-04	SCN1A, ATP1A2
neuromuscular process controlling posture	2	526.6×	2e-04	SCN1A, PRRT2
sodium ion transport	2	135.9×	0.002	SCN1A, ATP1A2
sodium ion transmembrane transport	2	101.5×	0.002	SCN1A, ATP1A2
olfactory cortex development	1	4213.0×	0.003	ATP1A2
negative regulation of short-term synaptic potentiation	1	4213.0×	0.003	PRRT2
negative regulation of SNARE complex assembly	1	2106.5×	0.004	PRRT2
regulation of glutamate uptake involved in transmission of nerve impulse	1	2106.5×	0.004	ATP1A2
negative regulation of calcium ion transmembrane transport	1	2106.5×	0.004	ATP1A2
negative regulation of striated muscle contraction	1	1404.3×	0.004	ATP1A2
regulation of calcium-dependent activation of synaptic vesicle fusion	1	1404.3×	0.004	PRRT2
negative regulation of heart contraction	1	1053.2×	0.005	ATP1A2
amygdala development	1	702.2×	0.007	ATP1A2
response to glycoside	1	601.9×	0.007	ATP1A2
regulation of striated muscle contraction	1	526.6×	0.007	ATP1A2
response to potassium ion	1	526.6×	0.007	ATP1A2
positive regulation of heart contraction	1	526.6×	0.007	ATP1A2
regulation of muscle contraction	1	421.3×	0.007	ATP1A2
synaptic vesicle fusion to presynaptic active zone membrane	1	421.3×	0.007	PRRT2
membrane depolarization during action potential	1	421.3×	0.007	SCN1A
L-ascorbic acid metabolic process	1	383.0×	0.007	ATP1A2
locomotion	1	383.0×	0.007	ATP1A2
neurotransmitter uptake	1	351.1×	0.007	ATP1A2
membrane depolarization during cardiac muscle cell action potential	1	351.1×	0.007	ATP1A2
cell communication by electrical coupling involved in cardiac conduction	1	351.1×	0.007	ATP1A2
regulation of respiratory gaseous exchange by nervous system process	1	324.1×	0.007	ATP1A2
negative regulation of cytosolic calcium ion concentration	1	324.1×	0.007	ATP1A2
relaxation of cardiac muscle	1	324.1×	0.007	ATP1A2
membrane repolarization	1	324.1×	0.007	ATP1A2
regulation of smooth muscle contraction	1	300.9×	0.007	ATP1A2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
SCN1A	MEXILETINE HYDROCHLORIDE
CACNA1A	NIMODIPINE
ATP1A2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
ATP1A2	5	4
CACNA1A	2	4
PRRT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
ATP1A2	49	Binding:49
CACNA1A	19	Binding:18, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SCN1A, CACNA1A, ATP1A2
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	1	PRRT2

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)
PRRT2	0	SCN1A

Clinical trials & evidence

Clinical trials

Clinical trials: 0.