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 |