Table 1.
The four major genes implicated in familial hemiplegic migraine
| Genes | Approximate number of cases and families reported in the literaturea | Percentage of affected subjects in four cohorts: a. Sutherland et al, 2020 [29] b. Pelzer et al, 2018 [21] c. Riant et al 2022 [30] d. Hiekkala et al, 2018 [31] |
Nature of causative mutations | Protein encoded and role | Involvement of the gene in other conditions [32] | |
|---|---|---|---|---|---|---|
| FHM1: CACNA1A | > 600 cases | 150 families |
a. 16/203 (7%) b. 107/? c. 26/697 (3.7%) d. 1/293 (0.34%) |
Missense mutations (Gain of function) Rare large exonic deletion or deletion in 5′ non coding end promoter |
Alpha-1 subunit of neuronal Cav2.1 (P/Q type) voltage-gated calcium channels ➔ Control of neuronal excitability at the presynaptic level of glutamatergic synapsis |
Episodic ataxia type 2 (loss of function) Spinocerebellar ataxia type 6 (SCA6) Lennox-Gastaut syndrome or Dravet syndrome, autism spectrum disorder (gain and loss of function) Possibly involved in Benign paroxysmal positional vertigo Dyskinesia Rett syndrome Paroxysmal tonic upward gaze |
| FHM2: ATP1A2 | > 900 cases | 160 families |
a. 20/203 (10%) b. 75/? c. 44/697 (6.3%) d. 2/293 (0.68%) |
Missense mutations Rare small deletions or truncating mutations, frameshift |
Catalytic alpha-2 subunit of the glial and neuronal ATP-dependent trans membrane Na+/K+-pump ➔ Clearance of extracellular K+ and production of a Na+ gradient necessary for glutamate reuptake |
Alternating hemiplegia of childhood Rapid-onset dystonia parkinsonim Cerebellar ataxia-areflexia-progressive optic atrophy Severe childhood epilepsies, encephalopathy and polymicrogyria Mental retardation |
| FHM3: SCN1A | > 120 cases | 20 families |
a. 4/203 (1.7%) b. 26/? c. 15/697 (2.1%) d. 0/293 |
Missense mutations (gain of function) |
Alpha-1 subunit of neuronal Nav1.1 voltage-gated sodium channels ➔ Propagation of action potentials of cortical neurons, especially in GABAergic inhibitory interneurons |
Early onset epileptic encephalopathies (cryptogenic generalized epilepsy, cryptogenic focal epilepsy, myoclonic–astatic epilepsy, Lennox-Gastaut syndrome, infantile spasm, Rasmussen encephalitis |
| FMH4: PRRT2 | > 120 cases | 40 families |
a. 5/203 (2.2%) b. 1/47 (2.1%) c. 30/697 (3.5%) d. not screened |
Missense mutations |
Pre-synaptic proline-rich transmembrane protein ➔ Interaction with the synaptosomal-associated protein 25 (SNAP25), suggesting a role in the fusion of synaptic vesicles to the plasma membrane |
Paroxysmal kinesigenic dyskinesia Benign familial infantile epilepsy Infantile convulsions with choreoathetosis Episodic ataxia Paroxysmal torticollis Intellectual disability |
aBased on research on Pubmed using keywords “name of the gene (example: CACNA1A)” and “migraine” or “name of the gene” and “headache”. Articles in other language than English, focusing on mice studies or other conditions than migraine were excluded. Each case where family history was not detailed was considered as sporadic and did not count as one family